Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate/High-Risk Pulmonary Embolism: Design of the Multicenter USAT IH-PE Registry and Preliminary Results.

Catheter-based revascularization procedures were developed as an alternative to systemic thrombolysis for patients with intermediate-high- and high-risk pulmonary embolisms. USAT IH-PE is a retrospective and prospective multicenter registry of such patients treated with ultrasound-facilitated, catheter-directed thrombolysis, whose preliminary results are presented in this study. The primary endpoint was the incidence of pulmonary hypertension (PH) at follow-up. Secondary endpoints were short- and mid-term changes in the echocardiographic parameters of right ventricle (RV) function, in-hospital and all-cause mortality, and procedure-related bleeding events. Between March 2018 and July 2023, 102 patients were included. The majority were at intermediate-high-risk PE (86%), were mostly female (57%), and had a mean age of 63.7 ± 14.5 years, and 28.4% had active cancer. Echocardiographic follow-up was available for 70 patients, and in only one, the diagnosis of PH was confirmed by right heart catheterization, resulting in an incidence of 1.43% (CI 95%, 0.036-7.7). RV echocardiographic parameters improved both at 24 h and at follow-up. In-hospital mortality was 3.9% (CI 95%, 1.08-9.74), while all-cause mortality was 11% (CI 95%, 5.4-19.2). Only 12% had bleeding complications, of whom 4.9% were BARC ≥ 3. Preliminary results from the USAT IH-PE registry showed a low incidence of PH, improvement in RV function, and a safe profile.

Space microgravity increases expression of genes associated with proliferation and differentiation in human cardiac spheres.

Efficient generation of cardiomyocytes from human-induced pluripotent stem cells (hiPSCs) is important for their application in basic and translational studies. Space microgravity can significantly change cell activities and function. Previously, we reported upregulation of genes associated with cardiac proliferation in cardiac progenitors derived from hiPSCs that were exposed to space microgravity for 3 days. Here we investigated the effect of long-term exposure of hiPSC-cardiac progenitors to space microgravity on global gene expression. Cryopreserved 3D hiPSC-cardiac progenitors were sent to the International Space Station (ISS) and cultured for 3 weeks under ISS microgravity and ISS 1 G conditions. RNA-sequencing analyses revealed upregulation of genes associated with cardiac differentiation, proliferation, and cardiac structure/function and downregulation of genes associated with extracellular matrix regulation in the ISS microgravity cultures compared with the ISS 1 G cultures. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes mapping identified the upregulation of biological processes, molecular function, cellular components, and pathways associated with cell cycle, cardiac differentiation, and cardiac function. Taking together, these results suggest that space microgravity has a beneficial effect on the differentiation and growth of cardiac progenitors.

AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.

BACKGROUND: Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation. METHODS: hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli. RESULTS: Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features-including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells. CONCLUSION: AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

Impact of body mass index in elderly patients treated with laparoscopic liver resection for hepatocellular carcinoma.

BACKGROUND: The impact of obesity on surgical outcomes in elderly patients candidate for liver surgery is still debated. AIM: To evaluate the impact of high body mass index (BMI) on perioperative and oncological outcome in elderly patients (> 70 years old) treated with laparoscopic liver resection for hepatocellular carcinoma (HCC). METHODS: Retrospective multicenter study including 224 elderly patients (> 70 years old) operated by laparoscopy for HCC (196 with a BMI < 30 and 28 with BMI ≥ 30), observed from January 2009 to January 2019. RESULTS: After propensity score matching, patients in two groups presented comparable results, in terms of operative time (median range: 200 min vs 205 min, P = 0.7 respectively in non-obese and obese patients), complications rate (22% vs 26%, P = 1.0), length of hospital stay (median range: 4.5 d vs 6.0 d, P = 0.1). There are no significant differences in terms of short- and long-term postoperative results. CONCLUSION: The present study showed that BMI did not impact perioperative and oncologic outcomes in elderly patients treated by laparoscopic resection for HCC.

Liver resection versus radiofrequency ablation in octogenarian patients for hepatocellular carcinoma: a propensity score multicenter analysis.

BACKGROUND: Liver resection (LR) and radiofrequency ablation (RFA) are considered curative options for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes after LR and RFA in octogenarian patients with HCC. MATERIALS AND METHODS: This multicenter retrospective study included 102 elderly patients (> 80 years old) treated between January 2009 and January 2019, who underwent LR or RFA for HCC (65 and 37 with, respectively). RESULTS: After Propensity Score Matching, the postoperative course of LR was burdened by a higher rate of complications than RFA group (64% vs 14%, respectively, p: 0.001). The LR group had also significantly longer operative time (207 ± 85 min vs 33 ± 49 min, p < 0.001) and postoperative hospital stays than the RFA group (7 d vs 2 d, p = 0.019). Overall survival at 1-, 2-, and 3-year were 86%, 86%, and 70% for the LR group and 82%, 64%, and 52% for the RFA group (p = 0.380). Disease-free survival at 1-, 2-, and 3-year were 89%, 74%, and 56% for the LR group, and 51%, 40%, and 40% for the RFA group (p = 0.037). CONCLUSION: Despite a higher rate of Dindo-Clavien I-II post-operative complications, a longer operative time and length of hospital stay, LR in octogenarian patients can provide comparable 90d mortality than RFA and better long-term outcomes.

Peri-operative score for elderly patients with resectable hepatocellular carcinoma.

BACKGROUND: Liver resection is the mainstay for a curative treatment for patients with resectable hepatocellular carcinoma (HCC), also in elderly population. Despite this, the evaluation of patient condition, liver function and extent of disease remains a demanding process with the aim to reduce postoperative morbidity and mortality. AIM: To identify new perioperative risk factors that could be associated with higher 90- and 180-d mortality in elderly patients eligible for liver resection for HCC considering traditional perioperative risk scores and to develop a risk score. METHODS: A multicentric, retrospective study was performed by reviewing the medical records of patients aged 70 years or older who electively underwent liver resection for HCC; several independent variables correlated with death from all causes at 90 and 180 d were studied. The coefficients of Cox regression proportional-hazards model for six-month mortality were rounded to the nearest integer to assign risk factors' weights and derive the scoring algorithm. RESULTS: Multivariate analysis found variables (American Society of Anesthesiology score, high rate of comorbidities, Mayo end stage liver disease score and size of biggest lesion) that had independent correlations with increased 90- and 180-d mortality. A clinical risk score was developed with survival profiles. CONCLUSION: This score can aid in stratifying this population in order to assess who can benefit from surgical treatment in terms of postoperative mortality.

Space microgravity improves proliferation of human iPSC-derived cardiomyocytes.

In microgravity, cells undergo profound changes in their properties. However, how human cardiac progenitors respond to space microgravity is unknown. In this study, we evaluated the effect of space microgravity on differentiation of human induced pluripotent stem cell (hiPSC)-derived cardiac progenitors compared with 1G cultures on the International Space Station (ISS). Cryopreserved 3D cardiac progenitors were cultured for 3 weeks on the ISS. Compared with 1G cultures, the microgravity cultures had 3-fold larger sphere sizes, 20-fold higher counts of nuclei, and increased expression of proliferation markers. Highly enriched cardiomyocytes generated in space microgravity showed improved Ca2+ handling and increased expression of contraction-associated genes. Short-term exposure (3 days) of cardiac progenitors to space microgravity upregulated genes involved in cell proliferation, survival, cardiac differentiation, and contraction, consistent with improved microgravity cultures at the late stage. These results indicate that space microgravity increased proliferation of hiPSC-cardiomyocytes, which had appropriate structure and function.

Prostatic artery embolization in people with spinal cord injury: a safe and effective technique to ease intermittent catheterization in case of concomitant benign prostatic hyperplasia.

STUDY DESIGN: Case series. OBJECTIVES: To assess the safety and efficacy of prostatic artery embolization (PAE) to reduce prostate volume (PV) and facilitate intermittent catheterization (IC) in individuals with concurrent benign prostatic hyperplasia (BPH) and spinal cord injury (SCI). SETTING: Italian tertiary referral center for people with SCI. METHODS: We retrospectively collected all data of individuals undergoing PAE from 2015 to 2020 because of BPH-related problems during IC. PAE was performed under local anesthesia with superselective catheterization of the prostatic arteries. Technical success was defined as bilateral embolization. We determined pre- and post-procedural PV by magnetic resonance imaging. RESULTS: We considered 10 cases with tetraplegia (n = 5) and paraplegia (n = 5). Nine (90%) procedures were technically successful, while we performed monolateral PAE in one case. The median pre-procedural PV was 61 mL. After 6 months, all patients experienced significant PV reduction (median: 19.6%), and 7/7 patients with indwelling urinary catheter started successfully IC. Neither intra- nor post-procedural complications occurred within a median follow-up of 33 months. CONCLUSIONS: PAE proved to be a safe and effective treatment for BPH to facilitate IC in people with SCI. Considering the minimal morbidity of PAE, further multi-center studies are mandatory to draw definitive conclusions and warrant its widespread adoption in this population.

Portal Steal Syndrome From a Large Linton's Splenorenal Shunt after Liver Transplantation: Successful Endovascular Management Through Off-Label Application of a 30 mm Amplatzer Cardiac Plug.

A 34-year-old patient underwent liver transplantation for progressive hepatic failure in the setting of congenital hepatic fibrosis. In past medical history, the patient had undergone splenectomy with proximal Linton's splenorenal surgical shunt creation for symptomatic portal hypertension with hypersplenism. The patient developed an early allograft dysfunction, with radiologic evidence of a reduced portal flow associated to portal steal from the patent surgical shunt. The patient was successfully treated through endovascular placement of a 30 mm Amplatzer cardiac plug at the origin of the splenic vein.

Laparoscopic surgery versus radiofrequency ablation for the treatment of single hepatocellular carcinoma ≤3 cm in the elderly: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) and radiofrequency ablation (RFA) represented potential treatments for patients with a single hepatocellular carcinoma (HCC) smaller than 3 cm. As the aging population soared, our study aimed to examine the advantage/drawback balance for these treatments, which should be reassessed in elderly patients. METHODS: A multicentric retrospective study compared 184 elderly patients (aged >70 years) (86 patients underwent LLR and 98 had RFA) with single ≤3 cm HCC, observed from January 2009 to January 2019. RESULTS: After propensity score matching (PSM), the estimated 1- and 3-year overall survival rates were 96.5 and 87.9% for the LLR group, and 94.6 and 68.1% for the RFA group (p = 0.001) respectively. The estimated 1- and 3-year disease-free survival rates were 92.5 and 67.4% for the LLR group, and 68.5 and 36.9% for the RFA group (p = 0.001). Patients with HCC of anterolateral segments were more often treated with laparoscopic resection (47 vs. 36, p = 0.04). The median operative time in the resection group was 205 min and 25 min in the RFA group (p = 0.01). Length of hospital stay was 5 days in the resection group and 3 days in the RFA group (p = 0.03). CONCLUSION: Despite a longer length of hospital stay and operative time, LLR guarantees a comparable postoperative course and a better overall and disease-free survival in elderly patients with single HCC (≤3 cm), located in anterolateral segments.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Radiofrequency ablation vs surgical resection in elderly patients with hepatocellular carcinoma in Milan criteria.

BACKGROUND: Surgical resection and radiofrequency ablation (RFA) represent two possible strategy in treatment of hepatocellular carcinoma (HCC) in Milan criteria. AIM: To evaluate short- and long-term outcome in elderly patients (> 70 years) with HCC in Milan criteria, which underwent liver resection (LR) or RFA. METHODS: The study included 594 patients with HCC in Milan criteria (429 in LR group and 165 in RFA group) managed in 10 European centers. Statistical analysis was performed using the Kaplan-Meier method before and after propensity score matching (PSM) and Cox regression. RESULTS: After PSM, we compared 136 patients in the LR group with 136 patients in the RFA group. Overall survival at 1, 3, and 5 years was 91%, 80%, and 76% in the LR group and 97%, 67%, and 41% in the RFA group respectively (P = 0.001). Disease-free survival at 1, 3, and 5 years was 84%, 60% and 44% for the LR group, and 63%, 36%, and 25% for the RFA group (P = 0.001).Postoperative Clavien-Dindo III-IV complications were lower in the RFA group (1% vs 11%, P = 0.001) in association with a shorter length of stay (2 d vs 7 d, P = 0.001).In multivariate analysis, Model for End-stage Liver Disease (MELD) score (> 10) [odds ratio (OR) = 1.89], increased value of international normalized ratio (> 1.3) (OR = 1.60), treatment with radiofrequency (OR = 1.46) ,and multiple nodules (OR = 1.19) were independent predictors of a poor overall survival while a high MELD score (> 10) (OR = 1.51) and radiofrequency (OR = 1.37) were independent factors associated with a higher recurrence rate. CONCLUSION: Despite a longer length of stay and a higher rate of severe postoperative complications, surgery provided better results in long-term oncological outcomes as compared to ablation in elderly patients (> 70 years) with HCC in Milan criteria.

Surgical Resection vs. Percutaneous Ablation for Single Hepatocellular Carcinoma: Exploring the Impact of Li-RADS Classification on Oncological Outcomes.

Background: Single hepatocellular carcinoma (HCC) benefits from surgical resection (SR) or US-guided percutaneous ablation (PA), although the best approach is still debated. We evaluated the impact of Li-RADS classification on the oncological outcomes of SR vs. PA as single HCC first-line treatment. Methods: We retrospectively and blindly classified treatment-naïve single HCC that underwent SR or PA between 2010 and 2016 according to Li-RADS protocol. Overall survival (OS), recurrence free survival (RFS) and local recurrence after SR and PA were compared for each Li-RADS subclass before and after propensity-score matching (PS-M). Results: Considering the general population, SR showed better 5-year OS (68.3% vs. 52.2%; p = 0.049) and RFS (42.5% vs. 29.8%; p = 0.002), with lower incidence of local recurrence (8.2% vs. 44.4%; p < 0.001), despite a significantly higher frequency of clinically-relevant complications (12.8% vs. 1.9%; p = 0.002) and a higher Comprehensive Complication Index (12.1 vs. 2.2; p < 0.001). Focusing on different Li-RADS subclasses, we highlighted better 5-year OS (67.1% vs. 46.2%; p = 0.035), RFS (45.0% vs. 27.0% RFS; p < 0.001) and lower incidence of local recurrence (9.7% vs. 48.6%; p < 0.001) after SR for Li-RADS-5 HCCs, while these outcomes did not differ for Li-RADS-3/4 subclasses; such results were confirmed after PS-M. Conclusions: Our analysis suggests a potential prognostic role of Li-RADS classification, supporting SR over PA especially for Li-RADS-5 single HCC.

Functional and molecular effects of TNF-α on human iPSC-derived cardiomyocytes.

Proinflammatory molecule tumor necrosis factor alpha (TNF-α) is predominantly elevated in cytokine storm as well as worsening cardiac function. Here we model the molecular and functional effects of TNF-α in cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC). We found that treatment of hiPSC-CMs with TNF-α increased reactive oxygen species (ROS) and caspase 3/7 activity and caused cell death and apoptosis. TNF-α treatment also resulted in dysregulation of cardiomyocyte function with respect to the increased abnormal calcium handling, calcium wave propagation between cells and excitation-contraction coupling. We also uncovered significant changes in gene expression and protein localization caused by TNF-α treatment. Notably, TNF-α treatment altered the expression of ion channels, dysregulated cadherins, and affected the localization of gap-junction protein connexin-43. In addition, TNF-α treatment up-regulated IL-32 (a human specific cytokine, not present in rodents and an inducer of TNF-α) and IL-34 and down-regulated glutamate receptors and cardiomyocyte contractile proteins. These findings provide insights into the molecular and functional consequences from the exposure of human cardiomyocytes to TNF-α. Our study provides a model to incorporate inflammatory factors into hiPSC-CM-based studies to evaluate mechanistic aspects of heart disease.

Endovascular approach for arteriovenous limb malformations: a single center experience.

BACKGROUND: To assess imaging findings, describe endovascular technical aspects and analyzed procedural outcomes in a population of patients underwent limb arteriovenous malformation (LAVMs). METHODS: From January 2015 to December 2018, all consecutive patients underwent an endovascular procedure for ICD-9-CM codex for arteriovenous malformation problems were retrospective reviewed. Among these, patients with LAVMs were selected. Demographic, preoperative imaging, interventional and postprocedural data were collected for each patient and procedure. The International Society of Vascular Anomalies, the Cho-Do angiographic classification and the Schobinger clinical stage were used to describe disease type, aspect and clinical severity. Angiographic and clinical outcomes were also described. RESULTS: During the study period, 76 intervention for AVMs were performed in 52 patients. Among these, 26 LAVMs were selected and analyzed in 21 patients (number of LAVMs per patient: 1.2±0.5), 14 affecting upper limbs, 17 lower limbs. Pain, discomfort and swelling were main symptoms reported (95%, 90% and 62%, respectively). Ultrasound scan, computed angiography tomography and magnetic resonance angiography were used - alone or in combination - as preoperative imaging in 67%, 62% and 48% of patients, respectively. Cho-Do class ≥3 was described in 70% of treated LAVMs and a Schobinger stage ≥2 in more than 90%. Ipsilateral femoral access with a 5F introducer was preferred. Selective embolization with glue was the most preferred technique (57%), in combination or not with microsphere embolization (19%) and/or direct nidus sclerotherapy (14%). Optimal and suboptimal results were achieved in 86% of cases. Further interventions were performed in 52% of cases, with more than two interventions in 29% of cases. CONCLUSIONS: Quality of life, clinical picture and anatomical structure are items of paramount importance during preoperative LAVMs endovascular treatment planning. Treatment must be focused on LAVMs type, minimizing invasiveness and number of interventions, although secondary intervention rate remains quite high.

Cryopreservation and CO2-independent culture of 3D cardiac progenitors for spaceflight experiments.

Space experimentation of cardiomyocyte differentiation from human induced pluripotent stem cells offers an exciting opportunity to explore the potential of these cells for disease modeling, drug discovery and regenerative medicine. Previous studies on the International Space Station were done with 2D non-cryopreserved cultures of cardiomyocytes being loaded and cultivated in spaceflight culture modules with CO2. Here we report the development of methods of cryopreservation and CO2-independent culture of 3D cardiac progenitors. The cryopreservation allows preparation and pretesting of the cells before spaceflight, makes it easier to transport the cell culture, reduces the impact of strong gravitational force exerted on the cells during the launch of spaceflight, and accommodates a more flexible working schedule for the astronauts. The use of CO2-independent medium with supplements supports cell growth and differentiation without a CO2 incubator. With these methods, we conducted a spaceflight experiment through the SpaceX-20 mission to evaluate the effect of microgravity on the survival and differentiation of 3D cardiac progenitors. Our cryopreserved cardiac progenitor spheres were successfully cultivated in a spaceflight culture module without CO2 for 3 weeks aboard the International Space Station. Beating cardiomyocytes were generated and returned to the earth for further study.

Liver resection vs radiofrequency ablation in single hepatocellular carcinoma of posterosuperior segments in elderly patients.

BACKGROUND: Liver resection and radiofrequency ablation are considered curative options for hepatocellular carcinoma. The choice between these techniques is still controversial especially in cases of hepatocellular carcinoma affecting posterosuperior segments in elderly patients. AIM: To compare post-operative outcomes between liver resection and radiofrequency ablation in elderly with single hepatocellular carcinoma located in posterosuperior segments. METHODS: A retrospective multicentric study was performed enrolling 77 patients age ≥ 70-years-old with single hepatocellular carcinoma (≤ 30 mm), located in posterosuperior segments (4a, 7, 8). Patients were divided into liver resection and radiofrequency ablation groups and preoperative, peri-operative and long-term outcomes were retrospectively analyzed and compared using a 1:1 propensity score matching. RESULTS: After propensity score matching, twenty-six patients were included in each group. Operative time and overall postoperative complications were higher in the resection group compared to the ablation group (165 min vs 20 min, P < 0.01; 54% vs 19% P = 0.02 respectively). A median hospital stay was significantly longer in the resection group than in the ablation group (7.5 d vs 3 d, P < 0.01). Ninety-day mortality was comparable between the two groups. There were no significant differences between resection and ablation group in terms of overall survival and disease free survival at 1, 3, and 5 years. CONCLUSION: Radiofrequency ablation in posterosuperior segments in elderly is safe and feasible and ensures a short hospital stay, better quality of life and does not modify the overall and disease-free survival.

Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells.

BACKGROUND: Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan-increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity. METHODS: hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms. RESULTS: Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+ handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-L-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-ß signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses. CONCLUSIONS: Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.