Predicting Hospital Readmissions in Patients Receiving Novel-Dose Sacubitril/Valsartan Therapy: A Competing-Risk, Causal Mediation Analysis.

Backgrounds: Our study aimed to identify and predict patients with heart failure (HF) taking novel-dose Sacubitril/Valsartan (S/V) at risk for all-cause readmission, as well as investigate the possible role of left ventricular reverse remodeling (LVRR). Methods and results: There were 464 patients recruited from December 2017 to September 2021 in our hospital with a median follow-up of 660 days (range, 17-1494). Competing risk analysis with Gray's Test showed statistically significant differences in all-cause readmission (p-value< .001) across the three different dose groups. Models 1 and 2 were developed based on the results of univariable competing risk analysis, least absolute shrinkage and selection operator approach, backward stepwise regression, and multivariable competing risk analysis. The internal verification (data-splitting method) indicated that Model 1 had better discrimination, calibration, and clinical utility. The corresponding nomogram showed that patients aged 75 years and above, or taking the lowest-dose S/V (≤50 mg twice a day), or diagnosed with ventricular tachycardia, or valvular heart disease, or chronic obstructive pulmonary disease, or diabetes mellitus were at the highest risk of all-cause readmission. In the causal mediation analysis, LVRR was considered as a critical mediator that negatively affected the difference of novel-dose S/V in readmission. Conclusions: A significant association was detected between novel-dose S/V and all-cause readmission in HF patients, in part negatively mediated by LVRR. The web-based nomogram could provide individual prediction of all-cause readmission in HF patients receiving novel-dose S/V. The effects of different novel-dose S/V are still needed to be explored further in the future.

GREM1 signaling in cancer: tumor promotor and suppressor?

GREMLIN1 (GREM1) is member of a family of structurally and functionally related secreted cysteine knot proteins, which act to sequester and inhibit the action of multifunctional bone morphogenetic proteins (BMPs). GREM1 binds directly to BMP dimers, thereby preventing BMP-mediated activation of BMP type I and type II receptors. Multiple reports identify the overexpression of GREM1 as a contributing factor in a broad range of cancers. Additionally, the GREM1 gene is amplified in a rare autosomal dominant inherited form of colorectal cancer. The inhibitory effects of GREM1 on BMP signaling have been linked to these tumor-promoting effects, including facilitating cancer cell stemness and the activation of cancer-associated fibroblasts. Moreover, GREM1 has been described to bind and signal to vascular endothelial growth factor receptor (VEGFR) and stimulate angiogenesis, as well as epidermal and fibroblast growth factor receptor (EGFR and FGFR) to elicit tumor-promoting effects in breast and prostate cancer, respectively. In contrast, a 2022 report revealed that GREM1 can promote an epithelial state in pancreatic cancers, thereby inhibiting pancreatic tumor growth and metastasis. In this commentary, we will review these disparate findings and attempt to provide clarity around the role of GREM1 signaling in cancer.

Impact of coronary artery disease in patients with hypertrophic cardiomyopathy.

BACKGROUND: Atherosclerotic coronary artery disease (CAD) often occurs concurrently with hypertrophic cardiomyopathy (HCM). However, the influence of concomitant CAD has not been fully assessed in patients with HCM. METHODS: Invasive or computed tomography coronary angiography was performed in 461 patients with HCM at our hospital to determine the presence and severity of CAD from March 2010 to April 2022. The primary end points were all-cause, cardiovascular, and sudden cardiac deaths. The survival of HCM patients with severe CAD was compared with that of HCM patients without severe CAD. RESULTS: Of 461 patients with HCM, 235 had concomitant CAD. During the median (interquartile range) follow-up of 49 (31-80) months, 75 patients (16.3%) died. The 5-year survival estimates were 64.3%, 82.5%, and 86.0% for the severe, mild-to-moderate, and no-CAD groups, respectively (log-rank, p = 0.010). Regarding the absence of cardiovascular death, the 5-year survival estimates were 68.5% for patients with severe CAD, 86.4% for patients with mild-to-moderate CAD, and 90.2% for HCM patients with no CAD (log-rank, p = 0.001). In multivariate analyses, severe CAD was associated with all-cause and cardiovascular death after adjusting for age, left ventricular ejection fraction, hypertension, and atrial fibrillation. CONCLUSIONS: This study showed a worse prognosis among HCM patients with severe CAD than among HCM patients without severe CAD. Therefore, timely recognition of severe CAD in HCM patients and appropriate treatment are important.

Risk factors for incomplete thrombosis in false lumen in sub-acute type B aortic dissection post-TEVAR.

There is scarce information about the risk factors for incomplete false lumen thrombosis (FLT) among type B aortic dissection (AD) patients, particularly in the sub-acute phase following thoracic endovascular aortic repair (TEVAR). We enrolled consecutive sub-acute type B AD patients at Xinqiao Hospital (Chongqing, China) from May 2010 to December 2019. Patients with severe heart failure, cancer, and myocardial infarction were excluded. The postoperative computed tomography angiography (CTA) data were extracted from the most recent follow-up aortic CTA. Multivariate logistic regressions were applied to identify the association between FLT and clinical or imaging factors. Fifty-five subjects were enrolled in our study. Twelve participants showed complete FLT, and 2 of these died during the follow-up, while 8 patients died in incomplete FLT group. In the multivariate analysis, maximum abdominal aorta diameter (OR 1.20, 95% CI 1.016-1.417 p = 0.032) and the number of branches arising from the false lumen (FL) (OR 15.062, 95% 1.681-134.982 p = 0.015) were significantly associated with incomplete FLT. The C-statistics was 0.873 (95% CI 0.773-0.972) for the model. The FL diameter (p < 0.001) was significantly shorter following TEVAR, while the true lumen diameter (p < 0.001) and maximum abdominal aorta diameter (p = 0.011) were larger after the aortic repair. There were 21.8% of sub-acute type B AD patients presented complete FLT post-TEVAR. Maximum abdominal aorta diameter and the number of branches arising from the FL were independent risk factors for incomplete FLT. The true lumen diameter, maximum abdominal aorta diameter, and FL diameter changed notably following TEVAR.

Prognostic Significance of B-Type Natriuretic Peptide in Patients With Left Ventricular Thrombus.

Background and Aims: There is sparse information on the prognostic value of B-type natriuretic peptide (BNP) for the outcomes in patients with left ventricular thrombus (LVT). Methods: Patients diagnosed with LVT by transthoracic echocardiography between November 2009 to July 2020 at our institution were included. The endpoints were all-cause mortality and systemic embolism. Results: Ninety-two subjects were finally included in the study. The mean age of the cohort was 56.73 ± 14.12, and 80.4% of the patients were male. The median BNP (1st quartile-3rd quartile) was 437.5 (112.74-1317.5). The total all-cause mortality rate was 30.44% (28/92), and the 1-year, 2-year, and 3-year cumulative survival rates were 85.4, 75.5, and 66.5%, respectively. Systemic embolism was identified in 10 subjects. COX multivariate analysis showed that Log BNP (HR, 4.16; 95%CI, 1.81-9.56; P = 0.001) and BMI (HR, 0.86; 95%CI, 0.73-0.99; P = 0.048) were significantly associated with all-cause mortality. In addition, patients with BNP levels in the upper median (≥ 437.5 pg/ml) had significantly higher all-cause mortality rate compared to those with lower median BNP (<437.5 pg/ml; P = 0.004). The area under the receiver operating characteristic curve for BNP and all-cause mortality was 0.71. In the linear trend test, BNP quartiles were significantly related to all-cause mortality in all models, and the P-values for trend in models 1, 2, and 3 were 0.005, 0.006, and 0.048, respectively. Conclusion: BNP level is a prognostic factor for all-cause mortality in LVT patients, and elevated BNP is indicative of a higher risk of LVT.

Incidence, Risk Factors, and Outcomes of Coronary Obstruction Following Valve-in-Valve Transcatheter Aortic Valve Replacement.

There is scant information about the incidence, risk factors, and outcomes of coronary obstruction (CO) following valve-in-valve transcatheter aortic valve replacement (VIV-TAVR). A meta-analysis of the published studies from January 2000 to April 2020 was conducted, and the endpoint was CO. A total of 2858 patients were enrolled in this study. The mean age was 77.7 ± 9.8, and 39.9% of them were female. The Society of Thoracic Surgeons (STS) score, European System for Cardiac Operative Risk Evaluation (EuroSCORE), and Logistic EuroSCORE were 8.9 ± 7.8, 16.0 ± 10.9, and 26.3 ± 16.3, respectively. The overall incidence of CO was 2.58%. CO incidence between patients with prior stented and stentless valves were significantly different (1.67% versus 7.17%), with an odds ratio (OR) of 0.25 and a 95% confidence interval (CI) of 0.14-0.44 (P < 0.00001). The first-generation valves were significantly associated with higher CO incidence compared with the second-generation valves (7.09% versus 2.03%; OR, 2.44; 95%CI, 1.06-5.62; P = 0.04), while no statistical difference was found between self-expandable valves and balloon-expandable valves (2.45% versus 2.60%; OR, 0.99; 95%CI, 0.55-1.79; P = 0.98). Virtual transcatheter to coronary ostia (VTC) distance (3.3 ± 2.1 mm, n = 29 versus 5.8 ± 2.4 mm, n = 169; mean difference, -2.70; 95%CI, -3.46 to -1.95; P < 0.00001) and the sinus of Valsalva (SOV) diameter (27.5 ± 3.8 mm, n = 23 versus 32.3 ± 4.0 mm, n = 101; mean difference, -3.80; 95%CI, -6.55 to -1.05; P = 0.007) were enormously shorter in patients with CO. The 24-hour, in-hospital, and 30-day mortality of patients with CO were 10.5%, 30.8%, and 37.1%, respectively. In conclusion, device selections, VTC distances, and SOV diameters may be important factors in assessing the CO risk in VIV-TAVR.

Prognostic Value of Preoperative Hemoglobin Levels for Long-Term Outcomes of Acute Type B Aortic Dissection Post-thoracic Endovascular Aortic Repair.

Background and Aims: There is scant information available about the prognostic value of preoperative hemoglobin (Hb) levels on the long-term outcomes of acute type B aortic dissection (ABAD) following thoracic endovascular aortic repair (TEVAR). Methods: A retrospective analysis of consecutive patients from 2010 to 2018 regarding the relationship between Hb level and long-term outcomes was conducted. The primary endpoint was all-cause mortality. Major adverse cardiovascular events (MACEs) included all-cause death, recurrent ruptures, and secondary procedures. Results: In total, 391 subjects treated by TEVAR were enrolled, with a mean age of 57.1 ± 12.0 years; 79.5% of them were male. Cox multivariate analysis showed that the preoperative Hb level was independently associated with all-cause death [adjusted hazard ratio (HR) 0.797 (per 1 g/dl), 95% confidence interval (CI) 0.693-0.918, p = 0.002] and MACEs (adjusted HR 0.795, 95% CI 0.672-0.871, p = 0.000). The area under the receiver operating characteristic curve of Hb for all-cause death and MACEs were 0.617 (95% CI 0.548-0.687, p = 0.008) and 0.617 (95% CI 0.551-0.684, p = 0.005), respectively. In the linear trend test, Hb concentration was significantly related to all-cause mortality (p for trend = 0.001) and MACEs (p for trend = 0.000). Moreover, in Kaplan-Meier analysis, lower Hb levels (< 12 g/dl) were significantly different from higher Hb (≥12 g/dl) levels for both all-cause death (log-rank p = 0.001) and MACEs (log-rank p = 0.001). Similar results were found when assessing the prognostic value of red blood cell count and anemia. Conclusions: Preoperative Hb may serve as a prognostic marker for long-range adverse outcomes for ABAD patients post-TEVAR.

Secreted BMP antagonists and their role in cancer and bone metastases.

Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. The interaction of BMP ligand with its receptors is carefully controlled by a diverse set of secreted antagonists that bind BMPs and block their interaction with their cognate BMP receptors. Perturbations in this BMP/BMP antagonist balance are implicated in a range of developmental disorders and diseases, including cancer. Here, we provide an overview of the structure and function of secreted BMP antagonists, and summarize recent novel insights into their role in cancer progression and bone metastasis. Gremlin1 (GREM1) is a highly studied BMP antagonist, and we will focus on this molecule in particular and its role in cancer. The therapeutic potential of pharmacological inhibitors for secreted BMP antagonists for cancer and other human diseases will also be discussed.

Dual-Energy CT-Derived Volumetric Iodine Concentration for the Assessment of Therapeutic Response after Microwave Ablation in a Rabbit Model with Intrahepatic VX2 Tumor.

PURPOSE: To evaluate whether changes in volumetric iodine concentration (VIC) could serve as a suitable predictor of therapeutic response to microwave (MW) ablation in a rabbit intrahepatic VX2 tumor model. MATERIALS AND METHODS: Sixteen intrahepatic VX2 tumors were transplanted in 8 New Zealand White rabbits treated with MW ablation. Contrast-enhanced dual-energy CT scans were obtained at baseline and follow-up. Therapeutic response assessment by modified Response Evaluation Criteria In Solid Tumors (mRECIST), Choi criteria, and VIC changes was performed. An intraclass correlation coefficient (ICC) was used to characterize consistency of assessment results among the criteria used. Technical success was evaluated with explant pathologic findings as a reference. Correlations between technical success and variations in diameter, CT density, and VIC were analyzed. RESULTS: Disease control was observed in 4, 8, and 10 of the 16 tumors per mRECIST, Choi criteria, and VIC changes, respectively. VIC exhibited strong consistency (ICC = 0.807, P < .0001) with Choi criteria. According to explant pathology, technical success was achieved in 10 of the 16 tumors. There was a moderate correlation between VIC changes and technical success (r = 0.532, P = .034), and no correlation was found between technical success and variations in diameter or CT density. CONCLUSIONS: Compared with mRECIST and Choi criteria, dual-energy CT-derived VIC allowed for better prediction of therapeutic response after MW ablation and could provide a potential imaging biomarker of tumor response to MW ablation in patients with hepatocellular carcinoma.