Magnetic Resonance for Differential Diagnosis of Left Ventricular Hypertrophy: Diagnostic and Prognostic Implications

Background: Left ventricular hypertrophy (LVH) may be due to different causes, ranging from benign secondary forms to severe cardiomyopathies. Transthoracic Echocardiography (TTE) and ECG are the first level examination for LVH diagnosis. Cardiac magnetic resonance (CMR) defines accurately LVH type, extent and severity. Objectives: to evaluate the diagnostic and prognostic role of CMR in patients with TTE and/or ECG evidence of LVH. Methods: We performed CMR in 300 consecutive patients with echocardiographic and/or ECG signs of LVH. Results: Overall, 275 patients had TTE evidence of LVH with initial suspicion of hypertrophic cardiomyopathy (HCM) in 132 (44%), cardiac amyloidosis in 41 (14%), hypertensive LVH in 48 (16%), aortic stenosis in 4 (1%), undetermined LVH in 50(16%). The initial echocardiographic diagnostic suspicion of LVH was confirmed in 172 patients (57.3%) and changed in 128 patients (42.7%, p<0.0001): the diagnosis of HCM increased from 44% to 71% of patients; hypertensive and undetermined LVH decreased significantly (respectively to 4% and 5%). CMR allowed a diagnosis in 41 out of 50 (82%) with undetermined LVH at TTE. CMR also identified HCM in 17 out of 25 patients with apparently normal echo but with ECG criteria for LVH. Finally, the reclassification of the diagnosis by CMR was associated with a change of survival risk of patients: after CMR reclassification no events occurred in patients with undetermined or hypertensive LVH. Conclusions: CMR changed echocardiographic suspicion in almost half of patients with LVH. In the subgroup of patient with abnormal ECG, CMR identified LVH (particularly HCM) in 80% of patients. This study highlights the indication of CMR to better characterize the type, extent and severity of LVH detected at echocardiography and suspected with ECG.

255 Tricuspid regurgitation in the community by routine echocardiography

Aims Tricuspid Regurgitation (TR) is quite frequent in the community and often overlooked in routine clinical practice. This study aims to convey the TR rate of diagnosis and impact on survival in a geographically defined population of an Italian referral centre, considering five different clinical contexts. Methods The study included consecutive outpatients with comprehensive echocardiography and complete clinical evaluation over 7 years of practice. Outpatients with TR greater than moderate were included, and the different clinical contexts evaluated: patients with concomitant significant mitral regurgitation (MR-TR), heart failure (HF-TR), previous open-heart surgery (postop-TR), pulmonary hypertension (PHTN-TR) and isolated TR (isolated-TR). Results Among all consecutive echocardiograms performed in routine practice (N=6797) in a geographically defined community, moderate or severe TR was found in 4.8% (N = 327; mean age 76±10, 56% female). Median follow-up was 6.1 [2.2–8.9] years. TR severity was an independent determinant of survival: risk ratio for mortality of severe TR vs. moderate was 1.72 [95% CI 1.06–2.77; P = 0.03] univariate and 1.76 [95% CI 1.02–3.01; P = 0.04] after adjusted for age, sex, MR, PHTN and EF. Only 2.8% of patients underwent tricuspid valve surgery during follow-up. Outpatients with MR-TR or HF-TR held the worst prognosis (Figure). As compared to isolated-TR, the mortality risk was 2.67 [95% CI 1.05–6.78; P = 0.04] for HF-TR and 2.04 [95% CI 1.00–4.14; P = 0.05] for MR-TR. Risk ratios for mortality vs. postop-TR were 3.66 [95% CI 1.19–11.26; P= 0.02] for HF-TR and 2.79 [95% CI 1.08–7.21; P = 0.03] for MR-TR. There was no interaction between the TR clinical context and the survival impact of TR (P=0.09). Conclusions Significant TR is frequent in our community, comparable to key epidemiological studies. TR severity independently impacts survival in all clinical settings, and it is associated with an absolute high event-rate when present with concomitant MR or HF. These results give importance to early diagnosis with grading to be performed through accurate echocardiography and renew the interest in new and safe, less invasive percutaneous intervention to improve patients' survival.

396 Echocardiography and magnetic resonance for differential diagnosis of left ventricular hypertrofy: diagnostic and prognostic implications

Aims Left ventricular hypertrophy (LVH) may be due to different causes, ranging from benign secondary forms to severe cardiomyopathies. Transthoracic Echocardiography (TTE) and ECG are the first level examination for LVH diagnosis. Cardiac magnetic resonance (CMR) defines accurately LVH type, extent and severity. To evaluate the diagnostic and prognostic role of CMR in patients with TTE and/or ECG evidence of LVH. Methods and results We performed CMR in 300 consecutive patients with echocardiographic and/or ECG signs of LVH. Overall, 275 patients had TTE evidence of LVH with initial suspicion of hypertrophic cardiomyopathy (HCM) in 132 (44%), cardiac amyloidosis in 41 (14%), hypertensive LVH in 48 (16%), aortic stenosis in 4 (1%), undetermined LVH in 50(16%). The initial echocardiographic diagnostic suspicion of LVH was confirmed in 172 patients (57.3%) and changed in 128 patients (42.7%, P < 0.0001): the diagnosis of HCM increased from 44% to 71% of patients; hypertensive and undetermined LVH decreased significantly (respectively, to 4% and 5%). CMR allowed a diagnosis in 41 out of 50 (82%) with undetermined LVH at TTE. CMR also identified HCM in 17 out of 25 patients with apparently normal echo but with ECG criteria for LVH. Finally, the reclassification of the diagnosis by CMR was associated with a change of survival risk of patients: after CMR reclassification no events occurred in patients with undetermined or hypertensive LVH. Conclusions CMR changed echocardiographic suspicion in almost half of patients with LVH. In the subgroup of patient with abnormal ECG, CMR identified LVH (particularly HCM) in 80% of patients. This study highlights the indication of CMR to better characterize the type, extent, and severity of LVH detected at echocardiography and suspected with ECG.

TAMI-11. INCREASED M1 MACROPHAGE INFILTRATION CORRELATED WITH POOR PROGNOSIS OF WHO IV GLIOMAS

BACKGROUND Gliomas are the malignancy with a poor prognosis. Our previous database mining study demonstrated that M1 macrophage infiltration predicted the survival of GBM patients. Here in this study, we further explored the findings. METHODS RNA-seq was performed on 90 WHO IV glioma tissue samples. The sequencing data was investigated with xCell for the cell infiltration levels, and the M1 macrophage infiltration was further analyzed for the prognostic prediction effect with overall survival (OS) data. Differentially expressed genes (DEGs) were calculated between groups and the hub genes were determined by the MCC models in Cytoscape. The survival risk score (SRS) calculating models were established by several machine learning methods, including the least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM), and linear discriminant analysis (LDA). RESULTS Compared with M1 macrophages none infiltration, WHO IV gliomas with M1 macrophages infiltration was associated with poor prognosis, and this result remained significant in multivariate analyses (hazard ratio [HR], 0.219; 95% CI, 0.047–0.723; P = 0.035). Protein-to-protein (PPI) network analysis of top 200 up-regulated DEGs determined 10 hub genes (P4HB, PDIA6, LAMB1, PRKCSH, CSF1, LAMB2, LGALS1, RCN1, CALU, and TNC). Further analysis determined that the 10 hub genes were enriched in the ECM-receptor interaction signaling pathway, and six out of the ten gene expressions were confirmed by immunohistochemistry staining. Based on the 6 genes, a survival risk score (SRS) was established by machine learning methods. SRS was able to distinguish the high-risk and low-risk WHO IV gliomas with an AUC = 0.80 [95% CI: 0.74 – 0.86, P < 0.01]. CONCLUSIONS M1 macrophage infiltration was an unfavorable prognostic biomarker for WHO IV gliomas. ECM-receptor interaction signaling pathway was involved in M1 macrophage infiltration. Hub genes in the signaling pathway could be the potential therapeutic targets for WHO IV gliomas.

Integrative eQTL-weighted hierarchical Cox models for SNP-set based time-to-event association studies

Background Integrating functional annotations into SNP-set association studies has been proven a powerful analysis strategy. Statistical methods for such integration have been developed for continuous and binary phenotypes; however, the SNP-set integrative approaches for time-to-event or survival outcomes are lacking. Methods We here propose IEHC, an integrative eQTL (expression quantitative trait loci) hierarchical Cox regression, for SNP-set based survival association analysis by modeling effect sizes of genetic variants as a function of eQTL via a hierarchical manner. Three p-values combination tests are developed to examine the joint effects of eQTL and genetic variants after a novel decorrelated modification of statistics for the two components. An omnibus test (IEHC-ACAT) is further adapted to aggregate the strengths of all available tests. Results Simulations demonstrated that the IEHC joint tests were more powerful if both eQTL and genetic variants contributed to association signal, while IEHC-ACAT was robust and often outperformed other approaches across various simulation scenarios. When applying IEHC to ten TCGA cancers by incorporating eQTL from relevant tissues of GTEx, we revealed that substantial correlations existed between the two types of effect sizes of genetic variants from TCGA and GTEx, and identified 21 (9 unique) cancer-associated genes which would otherwise be missed by approaches not incorporating eQTL. Conclusion IEHC represents a flexible, robust, and powerful approach to integrate functional omics information to enhance the power of identifying association signals for the survival risk of complex human cancers.

Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia

Monitoring of NPM1 mutant (mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as MRD transcript level <1-2% with <1-log change between any 2 positive samples collected after the end of treatment (EOT). As the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received at least 2 cycles of intensive chemotherapy were included if NPM1mut MRD positive in the bone marrow at the EOT and not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year: either spontaneously achieving complete molecular remission (30%) or retaining low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow up). Forty percent met the criteria for MP-LCN. Pre-emptive salvage therapy was found to significantly prolong relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-ITD at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.