Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Assessment of Native Myocardial T1 Mapping for Early Detection of Anthracycline-Induced Cardiotoxicity in Patients with Cancer: a Systematic Review and Meta-analysis.

Anthracycline antibiotic is one of the most effective anti-tumor drugs used to manage certain types of breast cancers, lymphomas, and leukemias. However, anthracyclines induce a dose-dependent cardiotoxicity that may progress to heart failure. Thus, using a sensitive predictor of early cardiac dysfunction in patients treated with anthracyclines can help detect subclinical cardiac dysfunction early and help initiate interventions to protect these patients. Among parameters of myocardial measure, cardiac magnetic resonance (CMR)-measured native myocardial T1 mapping is considered a sensitive and accurate quantitative measure of early subclinical cardiac changes, particularly cardiac inflammation and fibrosis. However, to understand the quality and the validity of the current evidence supporting the use of these measures in patients treated with anthracyclines, we aimed to conduct a systematic review of clinical studies of this measure to detect early myocardial changes in cancer patients treated with anthracyclines. The primary outcome was the level of native T1 mapping. We performed fixed-effects meta-analyses and assessed certainty in effect estimates. Of the 1780 publications reviewed (till 2022), 23 were retrieved, and 9 articles met the inclusion criteria. Our study showed that exposure to anthracycline was associated with a significant elevation of native myocardial T1 mapping from baseline (95% CI 0.1121 to 0.5802; p = 0.0037) as well as compared to healthy control patients (95% CI 0.2925 to 0.7448; p < 0.0001). No significant publication bias was noted on the assessment of the funnel plot and Egger's test. According to the Q test, there was no significant heterogeneity in the included studies (I2 = 0.0000% versus healthy controls and I2 = 14.0666% versus baseline). Overall, our study suggests that native myocardial T1 mapping is useful for detecting anthracycline-induced cardiotoxicity in patients with cancer.

Sex-based differences in short- and longer-term diet-induced metabolic heart disease.

Sex-based differences in the development of obesity-induced cardiometabolic dysfunction are well documented, however, the specific mechanisms are not completely understood. Obesity has been linked to dysregulation of the epitranscriptome, but the role of N6-methyladenosine (m6A) RNA methylation has not been investigated in relation to the sex differences during obesity-induced cardiac dysfunction. In the current study, male and female C57BL/6J mice were subjected to short- and long-term high-fat/high-sucrose (HFHS) diet to induce obesogenic stress. Cardiac echocardiography showed males developed systolic and diastolic dysfunction after 4 mo of diet, but females maintained normal cardiac function despite both sexes being metabolically dysfunctional. Cardiac m6A machinery gene expression was differentially regulated by duration of HFHS diet in male, but not female mice, and left ventricular ejection fraction correlated with RNA machinery gene levels in a sex- and age-dependent manner. RNA-sequencing of cardiac transcriptome revealed that females, but not males may undergo protective cardiac remodeling early in the course of obesogenic stress. Taken together, our study demonstrates for the first time that cardiac RNA methylation machinery genes are regulated early during obesogenic stress in a sex-dependent manner and may play a role in the sex differences observed in cardiometabolic dysfunction.NEW & NOTEWORTHY Sex differences in obesity-associated cardiomyopathy are well documented but incompletely understood. We show for the first time that RNA methylation machinery genes may be regulated in response to obesogenic diet in a sex- and age-dependent manner and levels may correspond to cardiac systolic function. Our cardiac RNA-seq analysis suggests female, but not male mice may be protected from cardiac dysfunction by a protective cardiac remodeling response early during obesogenic stress.

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.

Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

Repercusiones cardíacas en pacientes con pectus excavatum: puesta al día. Segunda parte / Cardiac repercussions in patients with pectus excavatum: update. Part two / Repercussões cardíacas em pacientes com pectus excavatum: atualização. Parte dois

El pectus excavatum (PEX) es una deformación de la pared torácica que obedece a una alteración de los cartílagos costales con el consiguiente hundimiento del esternón. Históricamente, se clasificaba como un defecto únicamente estético o cosmético, sin embargo, en los últimos años se han desarrollado nuevos métodos de estudio para la valoración de las repercusiones de esta patología. Existe cada vez más bibliografía que demuestra importantes repercusiones funcionales. Se realizó una puesta al día de las repercusiones cardíacas de la patología y un análisis de los artículos más relevantes de los últimos años. La evidencia actual permite afirmar que existe una afectación cardíaca por compresión esternal en la mayoría de los pacientes con PEX. Las afectaciones incluyen alteraciones anatomofuncionales (trastornos del ritmo, disminución del llenado ventricular), del volumen sistólico, aumento de la presión de la aurícula derecha, valvulopatías, compresión del ventrículo derecho, derrame pericárdico, entre otras. Todo lo cual permite concluir que el PEX puede presentar importantes alteraciones cardíacas que deben ser tenidas en cuenta a la hora de valorar los pacientes con esta patología.

Pectus excavatum (PEX) is a deformation of the chest wall caused by an alteration of the costal cartilages with the consequent collapse of the sternum. Historically, it had been classified as a solely aesthetic or cosmetic defect, however, in recent years new study methods have been developed to assess the repercussions of this pathology, with increasing bibliography showing important functional consequences. We updated the cardiac pathological repercussions and analyzed the most relevant articles of recent years. The current evidence suggests that there is cardiac involvement due to sternal compression in most patients with PEX. These affectations include anatomical functional alterations: rhythm disorders, decreased ventricular filling, decreased stroke volume, increased right atrial pressure, valve disease, right ventricular compression, pericardial effusion, among others. All of which enables us to conclude that PEX can present important cardiac alterations that must be taken into account when assessing patients with this pathology.

Pectus excavatum (PEX) é uma deformação da parede torácica decorrente de uma alteração das cartilagens costais com consequente colapso do esterno. Historicamente, foi classificado como um defeito exclusivamente estético ou cosmético, porém, nos últimos anos, novos métodos de estudo foram desenvolvidos para avaliar as repercussões dessa patologia, com crescente bibliografia mostrando importantes repercussões funcionais. Foi realizada uma atualização das repercussões cardíacas da patologia e análise dos artigos mais relevantes dos últimos anos. As evidências atuais permitem afirmar que há acometimento cardíaco por compressão esternal na maioria dos pacientes com PEX. As afecções incluem alterações anatomofuncionais: distúrbios do ritmo, diminuição do enchimento ventricular, diminuição do volume sistólico, aumento da pressão atrial direita, doença valvular, compressão do ventrículo direito, derrame pericárdico, entre outras. Tudo isso permite concluir que o PEX pode apresentar alterações cardíacas importantes que devem ser levadas em consideração na avaliação de pacientes com essa patologia.

Coronary microcirculation damage in anthracycline cardiotoxicity.

AIMS: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. METHODS AND RESULTS: Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. CONCLUSION: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

Physiological and pathological roles of protein kinase A in the heart.

Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind ß-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.

Cardio-Oncology Preclinical Models: A Comprehensive Review.

Cardiotoxicity is a common side effect induced by cancer therapies, which increases the risk of long-term morbidity and mortality in cancer survivors. To date, the mechanism leading to this toxicity is still unclear, thus complicating cardiac safety assessment and predictive factor identification. The advances in technology, particularly regarding radiation therapy and constant development of novel antineoplastic agents, require urgent development of efficient preclinical models to detect drug cardiotoxicity. A myriad of empirical preclinical models have been used to investigate cardiotoxicity, though with limited success. Recently, multicellular spheroid models have gained attention by mimicking the in vivo microenvironment. The aim of this review is to focus on the most relevant preclinical models used to assess antineoplastic drug- and radiotherapy-related cardiotoxicities, with an overview on their current use. It also aims to discuss the possible directions of translational research in the cardio-oncology field.

Lower muscular strength is associated with smaller left and right chambers and lower cardiac mass in the general population - The Sedentary's Heart.

BACKGROUND: The cardiac muscle has the ability to adapt to different loading conditions. We analyzed the associations of the age-related decreasing handgrip strength (HGS), a marker of muscular fitness, on cardiac structure and function in a community-based sample. METHODS: We performed cross-sectional analyses of 4646 subjects (2554 women; 55.0%) aged 20 to 93 years from two independent cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analyzed the associations of HGS with structural and functional left and right ventricular (LV and RV) and left atrial (LA) parameters as determined by echocardiography and magnetic resonance imaging (MRI) as well with log-transformed NT-proBNP values using multivariable-adjusted linear regression models. RESULTS: MRI data showed that a 1 kg lower HGS was associated with a 0.40 mL (95% confidence interval: 0.26 to 0.54; p < 0.001) lower LV end-diastolic volume, a 0.011 mm (0.005 to 0.018; p = 0.001) lower LV wall-thickness, a 0.59 g (0.43 to 0.75; p < 0.001) lower LV mass, a 0.58 mL/beat (0.43 to 0.74; p < 0.001) lower LV stroke volume, a 0.03 L/min (0.02 to 0.04; p < 0.001) lower LV cardiac output, a 0.48 mL (0.27 to 0.68; p < 0.001) lower LA end-diastolic volume, and a 1.02 mL (0.71 to 1.32) lower RV end-diastolic volume. Similar findings were observed for echocardiographic parameters. Moreover, lower HGS was associated with higher echocardiographic LV diastolic stiffness and NT-proBNP levels. CONCLUSIONS: In this large population-based sample, lower muscular fitness as assessed by HGS was associated with lower LV wall thickness and mass as well as with smaller chamber size, stroke volume and cardiac output of the LV, LA and RV. Moreover, HGS was inversely related to LV diastolic stiffness and NT-proBNP values. These outcomes might demonstrate the effects of an aging-related decrease in physical activity and lower muscular fitness on the heart - "the sedentary's heart".

Cardiac MRI shows an association of lower cardiorespiratory fitness with decreased myocardial mass and higher cardiac stiffness in the general population - The Sedentary's Heart.

BACKGROUND: The heart has the capacity to adapt to different demands. The pathophysiological mechanisms involved with sedentarism are not fundamentally the opposite of those related with physical activity and regular exercise. We investigated the impact of lower cardiorespiratory fitness (CRF) on heart's plasticity and function in a population-based setting. METHODS: We used data from 1165 participants (539 women; 46.3%) aged 21-81 years from two independent cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analyzed the cross-sectional associations of peak oxygen uptake (VO2peak), determined by symptom-limited cardiopulmonary exercise testing, with structural and functional left ventricular (LV) and left atrial (LA) parameters determined by magnetic resonance imaging (MRI) using multivariable- adjusted linear regression models. RESULTS: A 1 L/min lower VO2peak was associated with a 10.5 g (95% confidence interval: 8.00 to 12.9; p < 0.001) lower LV mass, a 14.8 mL (10.9 to 18.6; p < 0.001) lower LV end-diastolic volume, a 0.29 mm (0.19 to 0.40; p < 0.001) lower LV wall-thickness, a 8.85 mL/beat (6.53 to 11.2; p < 0.001) lower LV stroke volume, a 0.42 L/min (0.25 to 0.60; p < 0.001) lower LV cardiac output and a 7.51 mL (3.88 to 11.1; p < 0.001) lower LA end-diastolic volume. Moreover, there were no associations with a concentric or eccentric remodeling and LV and LA ejection fraction. CONCLUSIONS: Lower CRF was associated with a smaller heart, LV wall-thickness and mass, LV and LA stroke volume and cardiac output. Conversely, there was no association with LA and LV ejection fraction. Our cross-sectional observations are consistent with cardiac adaptations reflecting reduced volume loading demands of a sedentary lifestyle - "the sedentary's heart".

Cardiotoxic Effects of the Antineoplastic Doxorubicin in a Model of Metabolic Syndrome: Oxidative Stress and Transporter Expression in the Heart.

ABSTRACT: The aim of the present work was to examine whether metabolic syndrome-like conditions in rats with fructose (F) overload modify the cardiotoxic effects induced by doxorubicin (DOX) and whether the treatment altered the expression of P-gp, breast cancer resistance protein, and organic cation/carnitine transporters in the heart. Male Sprague-Dawley rats received either tap water (control group [C]; n = 16) or water with F 10% wt/vol (n = 16) during 8 weeks. Three days before being killed, the animals received a single dose of DOX (6 mg/kg, ip, md) (C-DOX and F-DOX groups) or vehicle (VEH; ISS 1 mL/kg BW; ip) (C-VEH and F-VEH groups) (n = 8 per group). F overload enhanced thiobarbituric acid-reactive substance levels in the left ventricle, and DOX injection further increased those values. DOX did not alter thiobarbituric acid-reactive substance production in C animals. DOX caused a decrease of 30% in the ejection fraction and a nearly 40% reduction in the fractional shortening in F animals, but not in C rats. Cardiac tissue levels of P-gp decreased by about 30% in F rats compared with the C groups. DOX did not modify cardiac P-gp expression. Breast cancer resistance protein and organic cation/carnitine transporter (OCTN 1/2/3) protein levels did not change with either F or DOX. It is suggested that DOX could cause greater cardiotoxicity in rats receiving F, probably due to enhanced cardiac lipid peroxidation and lower expression of cardiac P-gp. These results support the hypothesis that the cardiotoxicity of DOX could be increased under metabolic syndrome-like conditions or in other health disorders that involve cardiovascular risk factors.

Combined Usage of Trimetazidine With 3-Bromopyruvate May Lead to Cardiotoxicity by Activating Oxidative Stress and Apoptosis in Rats.

ABSTRACT: The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.

Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy.

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

The effect of triglycerides to high-density lipoprotein cholesterol ratio on the reduction of renal function: findings from China health and retirement longitudinal study (CHARLS).

BACKGROUND: Previous studies show that abnormal lipoprotein metabolism can increase the prevalence of chronic kidney disease (CKD). This study prospectively investigated the association of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio and renal dysfunction in the Chinese population. METHODS: This longitudinal cohort research examined 7,316 participants (age range: 22-93) from the China Health and Retirement Longitudinal Study (CHARLS), including 6,560 individuals with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 (normal renal function, NRF) group and 756 with eGFR < 60 mL/min/1.73 m2 (impaired renal function, IRF) group. In NRF group, reduction in renal function was defined as eGFR < 60 mL/min/1.73 m2 at exit visit and in IRF group, it was defined as decline in eGFR category, average eGFR decline > 5 mL/min/1.73 m2 per year or > 30 % decrease in eGFR from baseline. RESULTS: The study results showed that TG/HDL-C ratio was positively associated with the risk of renal function decline in the NRF group (OR 1.30, 95 %CI 1.03-1.65, P = 0.03) and the IRF group (OR 1.90, 95 %CI 1.21-3.23, P = 0.02) when adjusting for age, gender, obesity, diabetes, hypertension, waist circumference, drinking, smoking, history of heart disease and stroke, low-density lipoprotein cholesterol and eGFR category. Analysis of the IRF group indicated that relative to the group of TG/HDL-C < 1.60, the group of TG/HDL-C ≥ 2.97 had an increased risk for the decline of eGFR category (OR 1.89, 95 %CI 1.12-3.21, P = 0.02) and > 30 % decline in eGFR (OR 2.56, 95 %CI 1.05-6.38, P = 0.04). CONCLUSIONS: The high TG/HDL-C ratio was an independent risk factor for declining renal function in the Chinese population.

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation.

BACKGROUND: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. METHODS: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. RESULTS: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04-1.34], P=0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6-65.7], P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P<0.001; net reclassification index 1.05, P<0.001; integrated discrimination index 0.20, P<0.001). CONCLUSIONS: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02798731.

The Protective Effects of Coenzyme Q10 and Lisinopril Against Doxorubicin-Induced Cardiotoxicity in Rats: A Stereological and Electrocardiogram Study.

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

Cardiac anomalies associated with Escobar syndrome: A case report and a review of the literature.

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.