Heart Failure and Cardiomyopathies: CT and MR from Basics to Advanced Imaging.

Since 1997, heart failure (HF) has been designated as a new epidemic. However, it is not easy to find a proper definition since different descriptors are used in clinical practice. Moreover, HF is not a single clinical entity, and there is a close relationship between HF and all cardiomyopathies (CMs). This leads us to also consider accuracy in the characterization of CMs, which is essential to define the therapeutic process of HF patients. This narrative review aims to describe the main mechanisms leading to HF in different CMs, as well as the current diagnostic and prognostic advantages deriving from advanced imaging in the cardiac field.

Stress Perfusion Cardiac Magnetic Resonance in Long-Standing Non-Infarcted Chronic Coronary Syndrome with Preserved Systolic Function.

(1) Background: The impact of imaging-derived ischemia is still under debate and the role of stress perfusion cardiac magnetic resonance (spCMR) in non-high-risk patient still needs to be clarified. The aim of this study was to evaluate the impact of spCMR in a case series of stable long-standing chronic coronary syndrome (CCS) patients with ischemia and no other risk factor. (2) Methods: This is a historical prospective study including 35 patients with history of long-standing CCS who underwent coronary CT angiography (CCTA) and additional adenosine spCMR. Clinical and imaging findings were included in the analysis. Primary outcomes were HF (heart failure) and all major cardiac events (MACE) including death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, or resuscitated cardiac arrest. (3) Results: Mean follow-up was 3.7 years (IQR: from 1 to 6). Mean ejection fraction was 61 ± 8%. Twelve patients (31%) referred primary outcomes. Probability of experiencing primary outcomes based on symptoms was 62% and increased to 67% and 91% when multivessel disease and ischemia, respectively, were considered. Higher ischemic burden was predictive of disease progression (OR: 1.59, 95%CI: 1.18-2.14; p-value = 0.002). spCMR model resulted non inferior to the model comprising all variables (4) Conclusions: In vivo spCMR-modeling including perfusion and strain anomalies could represent a powerful tool in long-standing CCS, even when conventional imaging predictors are missing.

Unenhanced Cardiac Magnetic Resonance may improve detection and prognostication of an occult heart involvement in asymptomatic patients with systemic sclerosis.

Systemic sclerosis (SSc) is an uncommon autoimmune disease. Aim of the study was to detect the occult cardiac involvement in asymptomatic SSc patients of recent onset (indicative of a more aggressive disease) with unenhanced Cardiac Magnetic Resonance (CMR). Our historical prospective study included naïve SSc patients of recent onset. Modified Rodnan Skin Score (mRSS) and Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) were calculated. Cardiac volumes and global myocardial strain were assessed and also compared with healthy group values. Pericardial involvement was further recorded. Thirty-one patients met inclusion criteria (54 ± 12 years; 1 M). Mean duration of disease was 6.8 years. All patients showed preserved systolic function. Higher incidence of pericardial involvement was founded in patients with disease accrual damage (OR: 9.6, p-value 0.01). Radial and longitudinal strain values resulted significantly different between healthy and SSc patients. GRS and GLS showed an independent predictive validity on damage accrual (HR: 1.22 and 1.47, respectively). Best C-index for disease progression was reached when strain values and pericardial evaluation were added to conventional risk factors (0.97, p-value: 0.0001). Strain analysis by CMR-TT may show a high capability both in identifying early cardiac involvement and stratifying its clinical aggressiveness, regardless of the standard damage indices and CMR contrast-dependent biomarker.

Real-world clinical validity of cardiac magnetic resonance tissue tracking in primitive hypertrophic cardiomyopathy.

OBJECTIVE: Cardiac magnetic resonance (CMR) is an uncontested diagnostic tool for identifying and assessing hypertrophic cardiomyopathy (HCM) patients. Concerning the necessity to identify valid prognosticators for predicting the individual risk of clinical evolution, this study aimed to evaluate the clinical validity of CMR tissue tracking (TT) analysis in patients affected by primitive HCM in a real-world setting. METHODS: This historical prospective study included 33 patients. Diagnostic validity and clinical validation were assessed for strain values. CMR-TT diagnostic validity was studied comparing HCM patients with healthy control groups and phenotypic presentation of HCM. The impact of strain values and all phenotypic disease characteristics were assessed in a long-term follow-up study. RESULTS: The inter-reading agreement was good for all strain parameters. Significant differences were observed between the control group and HCM patients. Similarly, hypertrophic and LGE + segments showed lower deformability than healthy segments. The AUC of predictive model, including conventional risk factors for MACE occurrence and all strain values, reached 98% of diagnostic concordance (95% CI .94-1; standard error: .02; p value .0001), compared to conventional risk factors only (86%; 95% CI .73-99; standard error: .07; p value .002). CONCLUSION: In patients with primitive HCM, CMR-TT strain proves high clinical validity providing independent and non-negligible prognostic advantages over clinical features and traditional CMR markers.

Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex-vivo drug response data from 217 Chronic Lymphocytic Leukemia (CLL) cases. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to the known biomarkers. We validated its presence and clinical relevance in four independent cohorts (n=547 patients). We find that this axis captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL-PD was linked to the activation of mTOR-MYC-oxidative phosphorylation (OXPHOS) through transcriptomic, proteomic and single cell resolution analysis. CLL-PD is a key determinant of disease outcome in CLL. Our multi-table integration approach may be applicable to other tumors whose inter-individual differences are currently unexplained.

The protein landscape of chronic lymphocytic leukemia.

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry and integrated the results with genomic, transcriptomic, ex vivo drug response, and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X and MED12 to influence protein expression (false discovery rate [FDR] = 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal-component analysis (1055 and 542 differentially expressed proteins, FDR = 5%). Gene set enrichment analyses of CLL with trisomy 12 implicated B-cell receptor (BCR)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK, and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors, including Bruton tyrosine kinase and mitogen-activated protein kinase kinase (MEK) inhibitors. STAT2 was upregulated in unmutated IGHV CLL and trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a nonredundant layer of information in tumor biology and provides a protein expression reference map for CLL.

Cardiac magnetic resonance in arrhythmogenic cardiomyopathies.

Over the past few years, the approach to the 'arrhythmic patient' has profoundly changed. An early clinical presentation of arrhythmia is often accompanied by non-specific symptoms and followed by inconclusive electrocardiographic findings. In this scenario, cardiac magnetic resonance (CMR) has been established as a clinical tool of fundamental importance for a correct prognostic stratification of the arrhythmic patient. This technique provides a high-spatial-resolution tomographic evaluation of the heart, which allows studying accurately the ventricular volumes, identifying even segmental kinetic anomalies and properly detecting diffuse or focal tissue alterations through an excellent tissue characterization, while depicting different patterns of fibrosis distribution, myocardial edema or fatty substitution. Through these capabilities, CMR has a pivotal role for the adequate management of the arrhythmic patient, allowing the identification of those phenotypic manifestations characteristic of structural heart diseases. Therefore, CMR provides valuable information to reclassify the patient within the wide spectrum of potentially arrhythmogenic heart diseases, the definition of which remains the major determinants for both an adequate treatment and a poor prognosis. The purpose of this review study was to focus on the role of CMR in the evaluation of the main cardiac clinical entities associated with arrhythmogenic phenomena and to present a brief debate on the main pathophysiological mechanisms involved in the arrhythmogenesis process.

Coronary artery disease (CAD) extension-derived risk stratification for asymptomatic diabetic patients: usefulness of low-dose coronary computed tomography angiography (CCTA) in detecting high-risk profile patients.

BACKGROUND: As one of the most frequent risk factors for cardiovascular disease, type 2 diabetes mellitus (T2DM) is one of the largest causes of death. However, an acute cardiac presentation is not uncommon in diabetic patients, and the current investigative approach remains often inadequate. The aim of our study was to retrospectively stratify the risk of asymptomatic T2DM patients using low-dose 640-slice coronary computed tomography angiography (CCTA). MATERIALS AND METHODS: CCTA examinations of 62 patients (mean age, 65 years) with previous diagnosis of type 2 diabetes and without cardiac symptoms were analyzed. Image acquisition was performed using a 640-slice CT. Per-patient, per-vessel and per-plaque analyses were performed. Stratification risk was evaluated according to the ESC guidelines. The patients were followed up after 2.21 ± 0.56 years from CCTA examination. RESULTS: Coronary artery disease (CAD) was found in 58 patients (93.55%) presenting 290 plaques. Analysis of all samples showed severe-to-occlusive atherosclerosis in 24 patients (38.7% of cases). However, over the degree of stenosis, 23 patients were evaluated at high risk considering the extension of CAD. Good agreement was shown by the correlation of CAD extension/risk estimation and MACE incidence, according to a Kaplan-Meier survival analysis (p value = 0.001), with a 7.25-fold increased risk (HR 7.25 CI 2.13-24.7; p value = 0.002). CONCLUSION: Our study confirms the high capability of CCTA to properly stratify the CV risk of asymptomatic T2DM patients. Its use could be recommended if we consider how current investigative strategies to correctly assess these patients often seem inadequate.

In vivo radiation dosimetry and image quality of turbo-flash and retrospective dual-source CT coronary angiography.

PURPOSE: To compare measured radiation dose (MD), estimated radiation dose (ED) and image quality in coronary computed tomography between turbo-flash (TFP) and retrospective protocol (RP) and correlate MD with size-specific dose estimates (SSDE). MATERIALS AND METHODS: In this prospective study, we selected 68 patients (mean age, 59.2 ± 9.7 years) undergoing 192 × 2 dual-source CT (SOMATOM Force, Siemens) to rule out coronary artery disease. Thirty-one underwent TFP and 37 RP. To evaluate in vivo MD, thermoluminescent dosimeters were placed, superficially, at thyroid and heart level, left breast areola and left hemi-thorax. MD in each site, and ED parameters, such as volume CT dose index (CTDIvol), SSDE, dose length product (DLP), effective dose (E), were compared between two protocols with a t test. Image quality was compared between two protocols. Inter-observer agreement was evaluated with a kappa coefficient (k). In each protocol, MD was correlated with SSDE using a Pearson coefficient (r). RESULTS: Comparing TFP and RP, MD at thyroid (1.43 vs. 2.58 mGy; p = 0.0408), heart (3.58 vs. 28.72 mGy; p < 0.0001), left breast areola (3.00 vs. 24.21 mGy; p < 0.0001) and left hemi-thorax (2.68 vs. 24.03 mGy; p < 0.0001), CTDIvol, SSDE, DLP and E were significantly lower. Differences in image quality were not statistically significant. Inter-observer agreement was good (k = 0.796) in TFP and very good (k = 0.817) in RP. MD and SSDE excellently correlated with TFP (r = 0.9298, p < 0.0001) and RP (r = 0.9753, p < 0.0001). CONCLUSIONS: With TFP, MD, CTDIvol, SSDE, DLP and E were significantly lower, than with RP. Image quality was similar between two protocols. MD correlated excellently with SSDE in each protocol.

Coronary computed tomography angiography in the evaluation of intermediate risk asymptomatic individuals.

Cardiovascular disease is still one of the main causes of death and an early identification of coronary artery disease (CAD) remains the primary step in clinical management of patients with cardiovascular risk factor. Coronary computed tomography angiography (CCTA) has shown high sensitivity in CAD detection and could be helpful as screening method. The purpose of this study was to assess the prevalence of coronary artery disease detected by CCTA in asymptomatic patients with an intermediate risk of CAD. MATERIALS AND METHODS: We retrospectively selected 185 asymptomatic patients with an intermediate Framingan Risk Score (mean age was 62.3 ± 12.4 years); all patients underwent CCTA, using 640-slice CT. RESULTS: Atherosclerotic plaques were present in 112 out of 185 patients (60.5%); 56 subjects (30.2%) had mild stenosis, 49 (26.5%) moderate stenosis, only 3 patients (1.6%) had severe stenosis and in 4 cases (2.2%) the "blooming effect" did not allow for evaluation of the degree of stenosis. Among the positive cases, a high number of patients (44.6%) [50] showed coronary artery disease in one vessel, 33 patients (29.4%) in two vessels, 22 patients (19.6%) in three vessels and 5 patients in four vessels or more (4.5%). Patients with moderate stenosis were older, had hypertension in most cases, higher total cholesterol levels and more often were smokers. The radiation dose (mSv) dispensed to the patients was 3.7 ± 1.6 mSv. CONCLUSION: High prevalence of coronary stenosis detected by low-dose CCTA in patients not properly classified by the traditional methods of risk stratification commonly used in clinical practice emphasizes the need to extend the risk stratification to other diagnostic tools with higher capability to detect CAD.

DDX3X RNA helicase affects breast cancer cell cycle progression by regulating expression of KLF4.

DDX3X is a multifunctional RNA helicase with documented roles in different cancer types. Here, we demonstrate that DDX3X plays an oncogenic role in breast cancer cells by modulating the cell cycle. Depletion of DDX3X in MCF7 cells slows cell proliferation by inducing a G1 phase arrest. Notably, DDX3X inhibits expression of Kruppel-like factor 4 (KLF4), a transcription factor and cell cycle repressor. Moreover, DDX3X directly interacts with KLF4 mRNA and regulates its splicing. We show that DDX3X-mediated repression of KLF4 promotes expression of S-phase inducing genes in MCF7 breast cancer cells. These findings provide evidence for a novel function of DDX3X in regulating expression and downstream functions of KLF4, a master negative regulator of the cell cycle.

Uterine fibroid therapy using interventional radiology mini-invasive treatments: current perspective.

Uterine fibroids are common benign tumors of unclear etiopathology that affect the female reproductive tract. They are responsible for considerable morbidity and deterioration of life quality, and may have a negative impact on the reproductive system as well. Besides surgery aided by uterus-saving techniques, several minimally invasive procedures are now available within the field of interventional radiology that represent a valid solution for women who desire pregnancy and relief from disease-specific symptomatology. The main advantages offered by these techniques are low grade of invasiveness and short times of hospitalization. The most diffuse techniques are uterine artery embolization (UAE) and magnetic resonance-guided high-intensity focused ultrasound (MRgFUS). UAE is an endovascular procedure whose goal is obtained by provoking ischemia of the uterine vessels. MRgFUS is a thermoablation procedure that selectively ablates the symptomatic fibroids. In this review study, both procedures will be described, including a description of technical details, indications, contraindications, complications, and outcomes.

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

Bromodomains as therapeutic targets in cancer.

The malleability of the epigenome has long been recognized as a unique opportunity for therapeutic intervention. Interest in targeting components of the epigenetic machinery for therapeutic gain had initially been aimed at chromatin modifying enzymes. However, advances in medicinal chemistry have now made it possible to exploit protein-protein interactions at the chromatin interface. Bromodomains (BRD) are a conserved motif used by a large number of chromatin-associated proteins to recognize and bind acetylated histone tails. Small molecules with high specificity for the Bromodomain and Extra Terminal family of proteins (BRD2, BRD3, BRD4 and BRDT) have recently been shown to have remarkable pre-clinical efficacy in various malignancies. These findings have provided the impetus for exploring other BRD proteins as novel targets in cancer therapy.