Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far.

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters.

Effect of angiotensin-converting enzyme inhibitors versus that of angiotensin receptor blockers on survival in patients undergoing hemodialysis: a nationwide observational cohort study.

BACKGROUND: This study aimed to evaluate the patient survival rates based on the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in a large cohort of patients undergoing maintenance hemodialysis (HD). METHODS: Data from a national HD quality assessment program were used in this retrospective study. The patients were classified into four groups based on the use of renin-angiotensin system blockers (RASBs) as follows: No group, patients without a prescription of any anti-hypertensive drugs including RASBs; Other group, patients with a prescription of anti-hypertensive drugs excluding RASBs; ACEI group, patients with a prescription of an ACEI; and ARB group, patients with a prescription of an ARB. RESULTS: The 5-year survival rates in the no, other, ACEI, and ARB groups were 68.6%, 67.8%, 70.6%, and 69.2%, respectively. The ACEI group had the best patient survival trend among the four groups. In multivariable Cox regression analyses, no differences were observed between the ACEI and ARB groups. Among young patients and patients without diabetes or heart disease, the ACEI group had the best patient survival among the four groups. However, among patients with DM or heart disease, the ARB group had the best patient survival. CONCLUSIONS: Our study found that patients receiving ACEI and ARB had comparable survival. However, patients receiving ARB had better survival in the subgroups of patients with DM or heart disease, and patients receiving ACEI had better survival in the subgroup of young patients or patients without diabetes or heart disease.

A review regarding the article 'The cardioprotective potential of sodium-glucose cotransporter 2-inhibitors in breast cancer therapy-related cardiac dysfunction-A systematic review'.

Breast cancer is one of the most common types of cancer, representing 15 % of all new cancer cases in the United States. Approximately 12.4 % of all women will be diagnosed with breast cancer during their lifetime. In the past decades, a decrease in cancer-related mortality is evident as a result of early screening and improved therapeutic options. Nonetheless, breast cancer survivors face long-term treatment side effects, with cardiotoxicity being the most significant one, which lead to increased morbidity and mortality. Breast cancer patients are particularly susceptible to cancer therapeutics-related cardiac dysfunction (CTRCD) as treatment regimens include cardiotoxic drugs, primarily anthracyclines and anti-human epidermal growth factor receptor 2 (anti-HER2) agents (recombinant humanized monoclonal antibodies directed against HER2 such as trastuzumab and pertuzumab). Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Discontinuation of trastuzumab however, can lead to worse cancer outcomes. There have been case reports, registry-based, retrospective cohort-based and mechanistic studies suggesting the cardioprotective potential of SGLT2i in CTRCD. It is not known whether SGLT2i can prevent the development of incident HF or reduce the risk of HF in patients receiving trastuzumab with or without other concurrent anti-HER2 agent or sequential anthracycline for treatment of HER2 positive breast cancer. Based on these, there is now a call for randomized controlled trials to be performed in this patient cohort to advise guideline-directed therapy for CTRCD, which will in turn also provide detailed safety information and improve cancer and cardiovascular outcomes.

Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice.

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Golgi Protein 73 Promotes LPS-Induced Cardiac Dysfunction via Mediating Myocardial Apoptosis and Autophagy.

ABSTRACT: Sepsis-induced cardiac dysfunction represents a major cause of high mortality in intensive care units with limited therapeutic options. Golgi protein 73 (GP73) has been implicated in various diseases. However, the role of GP73 in lipopolysaccharide (LPS)-induced cardiac dysfunction is unclear. In this study, we established a sepsis-induced cardiac dysfunction model by LPS administration in wild-type and GP73 knockout ( GP73-/- ) mice. We found that GP73 was increased in LPS-treated mouse hearts and LPS-cultured neonatal rat cardiomyocytes (NRCMs). Knockout of GP73 alleviated myocardial injury and improved cardiac dysfunction. Moreover, depletion of GP73 in NRCMs relieved LPS-induced cardiomyocyte apoptosis and activated myocardial autophagy. Therefore, GP73 is a negative regulator in LPS-induced cardiac dysfunction by promoting cardiomyocyte apoptosis and inhibiting cardiomyocyte autophagy.

Role of Statin Therapy in Prevention of Anthracycline-Induced Cardiotoxicity: A Three Dimentional Echocardiography Study.

BACKGROUND: Recent advances in the treatment of breast cancer have resulted in improved overall cancer survival; however, cancer therapy related cardiac dysfunction is considered a major adverse effect of several chemotherapeutic agents, particularly anthracyclines. Hence, there is a need to develop proper cardioprotective strategies to limit myocardial injury following chemotherapy. OBJECTIVE: To evaluate the effect of statin therapy on prevention of anthracycline- induced cardiotoxicity in female patients with breast cancer. PATIENTS AND METHODS: The current study is a prospective, randomized, single-blind, placebo-controlled trial in which we enrolled a total of 110 female patients with newly diagnosed breast cancer who received anthracycline based chemotherapy. Patients were randomly assigned in 1:1 ratio into two groups, study group in which patients received 40 mg of oral atorvastatin and control group in which patients received placebo. A comprehensive echocardiographic examination was performed to all patients prior to receiving the chemotherapy and after 6 months, assessment of LV ejection fraction was done by 3D-echocardiography. All echocardiographers were blinded to all the patients' characteristics and assignment to either group. RESULTS: The mean age of patients assigned to the control group was 49.8±10.51 years old, while patients assigned to the intervention group had mean age of 47.84± 9.16 years old, both the control group and the intervention group were similar in demographic data and baseline clinical characteristics. There was a highly significant difference between the two groups regarding both the absolute LVEF assessed by 3D- echocardiography at 6 months and the percentage of change compared to baseline values, patients assigned to the control group had mean LVEF of 52.92% at 6 months with percentage of change reaching -7.06%, while those assigned to the intervention group had mean LVEF reaching 56.22% at 6 months with a percentage of change reaching -3.64% (P-value: 0.008 and 0.004 for the absolute value and percentage of change respectively). There was a significant difference between the two groups regarding incidence of development of cancer therapy related cardiac dysfunction (CTRCD); defined as drop in LVEF more than 10% and to a value below 53% assessed by 3D echocardiography, among the control group 15 patients (30%) developed CTRCD after 6 months from starting Anthracyclines based chemotherapy, while, among the intervention group only 6 patients (12%) developed CTRCD. (P-value= 0.027) CONCLUSION: Prophylactic use of atorvastatin may prevent the development of cancer therapy related cardiac dysfunction in breast cancer patients receiving anthracycline based chemotherapy.

Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.

OBJECTIVES: To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas. METHODS: This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events. RESULTS: One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m2 /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups. CONCLUSIONS AND RELEVANCE: Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.

Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.

Damage to the mitochondria may lead to serious conditions that are difficult to treat. Doxorubicin is one of the most widely used chemotherapeutic drugs for the treatment of malignancies in children and adults, and reportedly causes damage to the mitochondria. Unfortunately, the dangerous cardiac side effects of doxorubicin appear when the patient is in the midst of a vigorous fight against the disease, either by taking doxorubicin alone or in combination with other drugs. This study aimed to determine whether exogenous healthy and functional mitochondria are internalized by cells, can it help the survival of these cells, and can reduce cardiotoxicity. For this purpose, isolated, pure, and functional exogenous mitochondria were injected into the tail vein of a rat model of doxorubicin-induced cardiotoxicity. After that, the heart function of the rats and their antioxidant status, inflammatory markers, and histopathological examination were investigated. Our findings show that intravenous mitochondrial transplantation provided efficient mitochondrial uptake and reduced cardiotoxicity by reducing ROS production, lipid peroxidation, and inflammation. In addition, the levels of ATP and antioxidant enzymes increased after mitochondrial transplantation; therefore all of these complex processes resulted in the reduction of apoptosis and necrosis in rat heart tissue. These promising results open the way to more effective cancer treatment without the side effects of related drugs. Transplanting exogenous mitochondria probably enhances the cell's mitochondrial network, potentially treating mitochondria-related disorders such as cardiovascular and neurodegenerative diseases, although the exact relationship between mitochondrial damage and these conditions remains unclear.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction.

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Antineoplastic drugs inducing cardiac and vascular toxicity - An update.

With the improvement in cancer prognosis due to advances in antitumor therapeutic protocols and new targeted and immunotherapies, we are witnessing a growing increase in survival, however, at the same timeincrease in morbidity among cancer survivors as a consequences of the increased cardiovascular adverse effects of antineoplastic drugs. Common cardiovascular complications of antineoplastic therapies may include cardiac complications such as arrhythmias, myocardial ischemia, left ventricular dysfunction culminating in heart failure as well as vascular complications including arterial hypertension, thromboembolic events, and accelerated atherosclerosis. The toxicity results from the fact that these drugs not only target cancer cells but also affect normal cells within the cardiovascular system. In this article, we review the clinical features and main mechanisms implicated in antineoplastic drug-induced cardiovascular toxicity, including oxidative stress, inflammation, immunothrombosis and growth factors-induced signaling pathways.

Cancer Therapy-Related Cardiac Dysfunction in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy.

Background The risk of cardiac dysfunction for patients with prostate cancer undergoing androgen deprivation therapy (ADT) in the real-world setting remains unclear. Methods and Results A total of 1120 patients with prostate cancer and a baseline echocardiography scan were identified from Chang Gung Research Database between January 1, 2001 and December 31, 2019. Patients were treated with gonadotropin-releasing hormone agonist therapy, gonadotropin-releasing hormone antagonist therapy, or bilateral orchiectomy. Changes in left ventricular ejection fraction (LVEF) were further assessed in 421 patients using repeated measurements of LVEF before and during ADT treatment. The incidence of cancer therapy-related cardiac dysfunction (CT-RCD) was evaluated and defined as a ≥10% absolute decline in LVEF from baseline to a value of <53%. Among 421 patients undergoing ADT, LVEF declined from 66.3±11.3% to 62.5±13.6% (95% CI of mean difference: -5.0% to -2.7%) after a mean follow-up period of 1.6±0.8 years. CT-RCD occurred in 58 patients (13.7%) with a nadir LVEF of 40.3±9.1% after ADT. Lower baseline LVEF was significantly associated with CT-RCD (odds ratio, 1.07 [95% CI, 1.04-1.10]). The area under the curve of baseline LVEF for discriminating CT-RCD was 75.6%, with the corresponding optimal cutoff value of 64.5% (sensitivity, 79.3%; specificity, 67.2%). Conclusions ADT with gonadotropin-releasing hormone agonist therapy, gonadotropin-releasing hormone antagonist therapy, and bilateral orchiectomy were associated with an increased risk of CT-RCD in patients with prostate cancer. In addition, lower baseline LVEF was a significant predictor of CT-RCD in patients with prostate cancer undergoing treatment with ADT.

A comprehensive diagnostic approach to cardiac events in cancer patients receiving antineoplastic therapy: A systematic review.

Oncologic patients are vulnerable to a broad spectrum of cancer related cardiovascular complications during and/or after antineoplastic treatment. This article is dealing with the main drugs used in real world clinical practice, including conventional chemotherapy, targeted therapy, immunotherapy, radiotherapy and their potential cardiovascular toxicity. Diagnosis of cancer- related cardiovascular events requires thorough clinical evaluation, multimodality imaging techniques and cardiac biomarkers according to established guidelines of cardio-oncology. Multidisciplinary approach and individualized strategies are essential and crucial in confronting oncologic patients.

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Diagnostic Value of Three-Dimensional Speckle Tracking Imaging Strain Parameters for Detection of Cancer Chemotherapy-Related Cardiac Dysfunction: A Meta-Analysis. / Valor Diagnóstico de Parâmetros Tridimensionais de Strain de Imagem de Speckle Tracking para Detecção de Disfunção Cardíaca Relacionada à Quimioterapia do Câncer: Uma Metanálise.

BACKGROUND: Chemotherapeutic agents (e.g., anthracyclines, trastuzumab) commonly used for treating malignant tumors have been demonstrated to have cardiotoxic effects, which is associated with poor prognosis. Three-dimensional echocardiography has been used to predict cancer chemotherapy-induced cardiac dysfunction. OBJECTIVES: Evaluation of the diagnostic performance of strain parameters, global area strain (GAS), longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS) by meta-analysis. METHODS: Relevant studies were searched from the Embase, PubMed, and Web of Science databases. Statistical analysis was performed using Stata 12. The summary receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and corresponding 95% confidence interval for the four strain parameters were pooled. P<0.05 was considered statistically significant. RESULTS: Nine studies involving 650 participants were included. GAS and GLS showed significant diagnostic advantages over GCS and GRS. For GAS, the sensitivity was 0.85 (0.70, 0.93) and specificity was 0.82(0.78, 0.86) with PLR of 4.76 (3.55, 6.39) and NLR of 0.18 (0.09, 0.39) and an area under the curve (AUC) of 0.85 (0.82, 0.88). For GLS, the sensitivity was 0.81 (0.74, 0.86) and specificity was 0.81(0.68, 0.90) with PLR of 4.35(2.42, 7.80) and NLR of 0.23 (0.17, 0.33) and an AUC of 0.85 (0.82, 0.88). The GCS showed a sensitivity of 0.63 and a specificity of 0.79 with an AUC of 0.77. The GRS showed a sensitivity of 0.74 and a specificity of 0.66 with an AUC of 0.73. CONCLUSION: 3D-STI strain parameters GAS and GLS showed good performance in detecting early cardiac dysfunction in patients with tumors receiving chemotherapy.

FUNDAMENTO: Agentes quimioterápicos (por exemplo, antraciclinas, trastuzumabe) comumente usados para o tratamento de tumores malignos demonstraram ter efeitos cardiotóxicos, que estão associados a um prognóstico ruim. A ecocardiografia tridimensional tem sido usada para prever a disfunção cardíaca induzida pela quimioterapia do câncer. OBJETIVOS: Avaliação do desempenho diagnóstico de parâmetros de strain, área global de strain (AGS), strain longitudinal (SLG), strain circunferencial (SCG) e strain radial (SRG) por metanálise. MÉTODOS: Estudos relevantes foram pesquisados nas bases de dados Embase, PubMed e Web of Science. A análise estatística foi realizada usando Stata 12. O resumo da curva característica operacional do receptor, sensibilidade, especificidade, razão de verossimilhança positiva (RVP), razão de verossimilhança negativa (RVN), e o correspondente intervalo de confiança de 95% para os quatro parâmetros de strain foram combinados. P<0,05 foi considerado estatisticamente significativo. RESULTADOS: Nove estudos envolvendo 650 participantes foram incluídos. AGS e SLG mostraram vantagens diagnósticas significativas sobre SCG e SRG. Para AGS, a sensibilidade foi de 0,85 (0,70, 0,93) e a especificidade foi de 0,82 (0,78, 0,86) com RVP de 4,76 (3,55, 6,39) e RVN de 0,18 (0,09, 0,39) e uma área sob a curva (AUC) de 0,85 (0,82, 0,88). Para SLG, a sensibilidade foi de 0,81 (0,74, 0,86) e a especificidade foi de 0,81 (0,68, 0,90) com RVP de 4,35 (2,42, 7,80) e RVN de 0,23 (0,17, 0,33) e uma AUC de 0,85 (0,82, 0,88).OGCS mostrou uma sensibilidade de 0,63 e uma especificidade de 0,79 com uma AUC de 0,77.O SRG mostrou uma sensibilidade de 0,74e uma especificidade de 0,66 com umAUC de 0,73. CONCLUSÃO: Parâmetros 3D-STI de strain AGS e SLG mostraram bom desempenho na detecção precoce de disfunção cardíaca em pacientes com tumores recebendo quimioterapia.

A cardiotoxicity dataset for breast cancer patients.

This dataset is a result of the collaboration between the University of A Coruña and the University Hospital of A Coruña. It contains information about 531 women diagnosed with HER2+ breast cancer, treated with potentially cardiotoxic oncologic therapies. These treatments can cause cardiovascular adverse events, including cardiac systolic dysfunction, the development of which has important clinical and prognostic implications. The availability of good predictors may enable early detection of these cardiac problems. Variables such as age, weight and height are available for each patient, as well as some measures obtained from echocardiography, a technique used prior and during the treatment to check the structure and function of the heart. Among them, there is a functional variable that measures the myocardial velocity during the cardiac cycle. For patients that experienced cancer therapy-related cardiac dysfunction during the treatment period, time until its appearance is known. This dataset aims to enable the scientific community in conducting new research on this cardiovascular side effect.