Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

INTRODUCTION: Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. MATERIALS AND METHODS: We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. RESULTS: Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. CONCLUSIONS: Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up.

Global longitudinal strain: an early marker for cardiotoxicity in patients treated for breast cancer.

BACKGROUND: Patients treated with anthracyclines and trastuzumab are at increased risk of developing heart failure. Early diagnosis and treatment may prevent irreversible left ventricular (LV) dysfunction. This study investigates whether subclinical deterioration of global longitudinal strain (GLS) is a more reliable early predictor for LV dysfunction than three-dimensional (3D) LV ejection fraction (LVEF). METHODS: Adult patients receiving anthracyclines and trastuzumab for breast cancer who had serial echocardiographic follow-up were included in this retrospective study. The primary endpoint was the necessity to temporarily pause chemo- or immunotherapy due to declining LVEF (decline in 3D LVEF of > 10 percentage points to < 53%). Linear mixed-effects models were used to assess the longitudinal evolution of 3D LVEF and GLS over time. RESULTS: Fifty-one women were included, mean age 54 (50.5-57.6) years, with a total of 216 follow-up echocardiograms (mean follow-up 1.1 ± 0.45 years). GLS and 3D LVEF were significantly correlated (Spearman's rho: -0.36, p < 0.001). A decrease in GLS significantly predicted a lower LVEF on the subsequent echocardiogram [ß -0.6, 95% confidence interval (CI) (-1.0 to -0.2), p < 0.006]. Conversely, prior LVEF did not significantly predict GLS on the subsequent echocardiogram [ß -0.04, 95% CI -0.1 to -0.01, p = 0.12]. Nine patients reached the primary endpoint. On average, patients who reached the primary endpoint had a relative decrease of 15% GLS at day 205 and an absolute 10% decrease of LVEF to LVEF < 53% at day 235. DISCUSSION: GLS is able to identify subclinical LV dysfunction earlier than 3D LVEF measurement in women undergoing treatment for breast cancer with anthracyclines followed by trastuzumab.

Cardiovascular Disorder after Cardiotoxic Non-Hodking's Lymphoma Treatment: A Case Report.

The non-Hodgkin's lymphomas are a diverse group of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality. Patients treated with mediastinal radiotherapy and/or anthracycline-containing chemotherapy are known to have increased risks of coronary heart disease, valvular heart disease, and heart failure. This may be the result of cancer treatment cardiotoxicity or may be due to accelerated development of cardiovascular disease. We presented 41-year-old male who was admitted to the hospital because of congestive heart failure. He has a medical history of non-Hodgkin's lymphoma treated with anthracycline-based chemotherapy and mediastinal radiotherapy almost 20 years ago. Echocardiography showed significant aortic valve stenosis, thickened and fibrotic pericardium. Coronary angiography showed diffuse three-vessel coronary artery disease. The patient was referred for surgical treatment. Aortic valve replacement, coronary artery bypass grafting and pericardiectomy were successfully performed, symptoms of heart failure reduced.

Design, synthesis and mechanistic study of novel diarylpyrazole derivatives as anti-inflammatory agents with reduced cardiovascular side effects.

Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via recombinant enzyme assays to explore their anti-inflammatory activities and cardiovascular safety profiles. Comprehensively, the structures of the synthesized compounds were established via spectral and elemental analyses, followed by the assessment of both their in vitro COX inhibitory and in vivo anti-inflammatory activities. The most active compounds as COX inhibitors were further evaluated for their in vitro 5-LOX and sEH inhibitory activities, alongside with their in vivo analgesic and ulcerogenic effects. Compounds 6d and 11f showed excellent inhibitory activities against both COX-2 and sEH (COX-2 IC50 = 0.043 and 0.048 µM; sEH IC50 = 83.58 and 83.52 µM, respectively). Moreover, the compounds demonstrated promising results as anti-inflammatory and analgesic agents with considerable ED50 values and gastric safety profiles. Remarkably, the most active COX inhibitors 6d and 11f possessed improved cardiovascular safety profiles, if compared to celecoxib, as shown by the laboratory evaluation of both essential cardiac biochemical parameters (troponin-1, prostacyclin, tumor necrosis factor-α, lactate dehydrogenase, reduced glutathione and creatine kinase-M) and histopathological studies. On the other hand, docking simulations confirmed that the newly synthesized compounds displayed sufficient structural features required for binding to the target COX-2 and sEH enzymes. Also, in silico ADME studies prediction and drug-like properties of the compounds revealed favorable oral bioavailability results. Collectively, the present work could be featured as a promising future approach towards novel selective COX-2 inhibitors with declined cardiovascular risks.

Effects of grapeseed extract on doxorubicin-induced cardiotoxicity in rats.

BACKGROUND: Doxorubicin (DX) is used for the treatment of many types of cancer; however, a side effect of this agent is cardiotoxicity, which may lead to cardiomyopathy or cardiac failure. Oxidative stress is thought to play a major role in the development of cardiotoxic effects. Proanthocyanidins found in grapeseed (GS) extract may inhibit chemically induced lipid peroxidation and apoptosis caused by oxidative stress. We aimed to investigate the cardioprotective effects of GS extract against DX-induced cardiotoxicity. METHODS: A total of 28 male Sprague Dawley rats were grouped to receive: (a) standard nutrition (n = 7); (b) standard nutrition with an additional dose of 10 mg/kg DX (n = 7); (c) standard nutrition plus 100 mg/kg/day of GS (n = 7); (d) standard nutrition with 100 mg/kg/day of GS plus a single dose of 10 mg/kg DX. After 35 days the rats were decapitated and blood samples were taken for biochemical testing. Cardiac tissue samples were prepared for microscopy and histopathological evaluation. RESULTS: Rats in the DX group exhibited significant elevations in biomarkers such as troponin and NT-proBNP as well as in oxidative stress markers compared with all other groups. Histopathological examination corroborated these findings by demonstrating significant and severe structural injury in the cardiac tissue of DX rates. Moreover, rats in the DX + GS group had significantly lower cardiac injury than rats in the DX group according to both biochemical (troponin and NT-proBNP) and histopathological analyses. Serum malondialdehyde levels (a marker of oxidative stress) in the DX + GS rats were significantly lower than in the DX rats. CONCLUSION: Our findings suggest that GS may reduce the severity of DX-induced cardiotoxicity and thus has the potential to prevent cardiac injury in this setting.

[Forensic characteristics of the cardio-toxic effect of organophosphorus compounds]. / Sudebno-meditsinskaya kharakteristika kardiotoksicheskogo deistviya fosfororganicheskikh soedinenii.

Objective - to identify the morphological equivalents of the cardiotoxic action of organophosphate poisoning. It was studied 110 fatal organophosphate poisonings in toxicogenic and somatogenic stages. The study of the heart was a comprehensive in term of clinical, biochemical, histological, micromorphometric, histochemical and histoenzymological approaches. We have identified a complex of deep metabolic disorders and necrobiotic changes in the heart muscle and the level of cholinesterase activity inhibition in the cholinergic structures of the heart in the toxicogenic and somatogenic stages of fatal organophosphate poisoning.

Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Clinical or subclinical cardiotoxicity is a concern for cancer patients receiving anthracycline-based chemotherapy. Carvedilol is promising for preventing anthracycline-induced cardiotoxicity (AIC). This review appraised the preventive effects of carvedilol against AIC based on randomized controlled trials (RCTs). METHODS: The Cochrane Collaboration Central Register of Controlled Trials, PubMed, and Embase databases were searched from inception to March 27, 2018. RCTs using carvedilol for the prevention of AIC were selected. Risk of bias and methodological quality were assessed. Meta-analysis was conducted, when applicable, for the trial endpoints; otherwise the data were analyzed descriptively. RESULTS: Nine RCTs comprising 717 patients were selected. The risk of bias was unclear and the methodological quality differed substantially. Data pooling of five eligible studies indicated no decreased mortality in patients receiving carvedilol (risk difference = -0.02, 95% CI: -0.07-0.04, p = 0.57, I2 = 44%). The impact on the incidence of left ventricular systolic dysfunction (LVSD) was inconsistently reported but meta-analysis was not applicable due to discordant LVSD definitions. Data pooling of eight studies and a subgroup analysis indicated a higher left ventricular ejection fraction (LVEF) with substantial heterogeneity in the carvedilol group (mean difference [MD] = 5.23, 95% CI: 2.20-8.27, p = 0.0007, I2 = 95%, and MD = 4.65, 95% CI: 0.67-8.64, p = 0.02, I2 = 90%, respectively). Further analysis of echocardiographic parameters and biomarkers showed weak evidence of improvement in diastolic function and troponin I level by carvedilol administration. CONCLUSION: Preventive use of carvedilol in patients undergoing anthracycline-based chemotherapy may be associated with a reduced incidence of LVSD, higher LVEF value, better diastolic function, and lower troponin I level. RCTs with larger sample size and longer follow-up are needed to verify these findings.

Palicourea marcgravii (Rubiaceae) poisoning in cattle grazing in Brazil.

Palicourea marcgravii is the most important poisonous plant of cattle in Brazil. It contains monofluoroacetic acid and causes sudden death associated with exercise. Herein, we describe the temporal and spatial distribution of the toxic disease. The survey was based on the epidemiological, clinical, and pathological data of the Setor de Anatomia Patológica (SAP) of the Universidade Federal Rural do Rio de Janeiro (UFRuralRJ) to report outbreaks of poisoning by P. marcgravii, from 1953 to 2018. Clinical signs were peracute and included labored breathing, loss of balance, muscle tremors, lateral recumbency, and limb paddling. Gross lesions such as congestion of large vessels and edema and pulmonary congestion were observed. Multifocal areas of vacuolar hydropic degeneration of distal contorted tubule cells with nuclear pyknosis were observed in the kidneys. The plant is found in forests, and the poisoning occurs mainly after clearing forests for pasture, in areas of natural forest recovery called "capoeira," which provide a favorable environment for maintaining P. marcgravii growth. Outbreaks of P. marcgravii poisoning coincided with periods of creation of large deforested pastures in the Southeast and Midwest regions of Brazil, and the poisoning should be considered an additional risk after deforestation. The most effective prophylaxis is fencing off the forest areas that contain these plants.

Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α.

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1ß mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1ß), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.

Cardiac-Specific Cre Induces Age-Dependent Dilated Cardiomyopathy (DCM) in Mice.

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system.

NSAIDs and heart failure: A dangerous relationship.

One of the potential cardiotoxic action of anti-inflammatory drugs is the occurrence of heart failure (HF), due to their effects on fluid retention and blood pressure. The risk of hospitalization for HF is roughly doubled for both Coxibs, cyclooxygenase-1 (COX-1) and cyclooxygenase- 2 (COX-2) inhibitors, and all the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are also associated with a risk of vascular thrombosis, which for NSAIDs is different in relation to their different ability to inhibit COX-1 and COX-2. The cardiovascular toxicity of these drugs in the direction of HF follow different pathways respect to their related vascular thrombosis toxicity and involves, in particular, the renal prostaglandins, PGE2 and prostacyclin, mostly synthesized by COX-2. In the kidneys the PGs perform a direct vasodilatory action, e.g. by means of non-contrasting angiotensin mechanisms, and for this reason nimesulide effects on renal microcirculation are independent from the prevalence of intrarenal renin angiotensin aldosterone system (RAAS) activity. Conversely, nimesulide reduces sodium tubular urinary flow only in presence of intrarenal RAAS.

Neurotoxic and cardiotoxic effects of pyrogallol on catfish (Clarias gariepinus).

Pyrogallol, a botanical hydrolysable tannin, has diverse medical and industrial applications. Its impact on aquatic ecosystems and fish health has been previously studied, revealing histopathological, immunological, biochemical, and haematological alterations in African catfish (Clarias gariepinus). In this study, the neurotoxic potential of pyrogallol was assessed through a 15-day exposure of catfish to concentrations of 1, 5, or 10 mg/L. Enzyme activities such as acetylcholinesterase (AchE), monoamine oxidase (MAO), aldehyde oxidase (AO), and nitric oxide (NO) were measured in serum and brain, along with histopathological examinations in the brain and heart. Pyrogallol exposure led to decreased AchE activity in the brain and serum, increased serum MAO activity, elevated AO in both brain and serum, and suppressed NO levels. Morphological abnormalities and dose-dependent pathological alterations were observed in the brain and heart, including neuropile deformities, shrunken Purkinje cells, cardiomyocyte degeneration, and increased collagen fibers. This suggests that pyrogallol induces adverse effects in fish.

The efficacy and safety of exercise regimens to mitigate chemotherapy cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cardiotoxicity is one of the most common adverse events of the chemotherapy. Physical exercise was shown to be cardioprotective. We aim to estimate the efficacy and safety of exercise in cancer patients receiving cardiotoxic chemotherapy. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, SCOPUS, Cochrane, Clinical Trials.gov, and MedRxiv through July 17th, 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), with a 95% confidence interval (CI). PROSPERO ID: CRD42023460902. RESULTS: We included thirteen RCTs with a total of 952 patients. Exercise significantly increased VO2 peak (MD: 1.95 with 95% CI [0.59, 3.32], P = 0.005). However, there was no significant effect regarding left ventricular ejection fraction, global longitudinal strain, cardiac output, stroke volume, left ventricular end-diastolic volume, left ventricular end-systolic volume, E/A ratio, resting heart rate, peak heart rate, resting systolic blood pressure, and resting diastolic blood pressure. Also, there was no significant difference regarding any adverse events (AEs) (RR: 4.44 with 95% CI [0.47, 41.56], P = 0.19), AEs leading to withdrawal (RR: 2.87 with 95% CI [0.79, 10.43], P = 0.11), serious AEs (RR: 3.00 with 95% CI [0.14, 65.90], P = 0.49), or all-cause mortality (RR: 0.25 with 95% CI [0.03, 2.22], P = 0.21). CONCLUSION: Exercise is associated with increased VO2 peak in cancer patients receiving cardiotoxic chemotherapy. However, there was no significant difference between exercise and usual care regarding the echocardiographic and safety outcomes.

Intrathecal ropivacaine versus bupivacaine in a non-obstetric population- A meta-analysis and trial sequential analysis.

Background and Aims: Intrathecal bupivacaine is used for anaesthesia and analgesia but is associated with hypotension. Ropivacaine is an alternative drug that may have fewer cardiotoxic and neurotoxic events. This meta-analysis investigated whether intrathecal ropivacaine is associated with reduced hypotension as compared to bupivacaine. Methods: The meta-analysis is registered in the International Prospective Register of Systematic Reviews (PROSPERO). The databases PubMed, Cinahl Plus, Google Scholar, and Scopus were searched, and papers from January 1980 to January 2023 were deemed eligible and filtered using predetermined inclusion and exclusion criteria. The primary outcome was the incidence of hypotension. Secondary outcomes were the duration of sensory block, duration of motor block, incidence of bradycardia, ephedrine usage, and duration of analgesia. Jadad scores were used to evaluate the quality of the papers. RevMan statistical software® utilised inverse variance and a random effect model to calculate the standardised mean difference with 95% confidence intervals for continuous variables and the Mantel-Haenszel test and the random effect model to calculate the odds ratio for dichotomous variables. Results: Thirty-three papers, including 2475 patients in total, were included. The Jadad score was between 1 and 5. The incidence of hypotension was significantly higher with intrathecal bupivacaine than with ropivacaine (P = 0.02). The duration of sensory block (P < 0.001) and motor block (P < 0.001) was prolonged with intrathecal bupivacaine. The duration of analgesia favoured intrathecal bupivacaine (P = 0.003). Conclusion: Intrathecal ropivacaine has a reduced incidence of hypotension and a reduced duration of sensory block compared to bupivacaine.

Indole-3-acetic acid induced cardiogenesis impairment in in-vivo zebrafish via oxidative stress and downregulation of cardiac morphogenic factors.

Plant growth regulators (PGRs) are increasingly used to promote sustainable agriculture, but their unregulated use raises concerns about potential environmental risks. Indole-3-acetic acid (IAA), a commonly used PGR, has been the subject of research on its developmental toxicity in the in-vivo zebrafish model. IAA exposure to zebrafish embryos caused oxidative stress, lipid peroxidation, and cellular apoptosis. The study also revealed that critical antioxidant genes including sod, cat, and bcl2 were downregulated, while pro-apoptotic genes such as bax and p53 were upregulated. IAA exposure also hampered normal cardiogenesis by downregulating myl7, amhc, and vmhc genes and potentially influencing zebrafish neurobehavior. The accumulation of IAA was confirmed by HPLC analysis of IAA-exposed zebrafish tissues. These findings underscore the need for further study on the potential ecological consequences of IAA use and the need for sustainable agricultural practices.

Left ventricular diastolic function and cardiotoxic chemotherapy.

BACKGROUND: Left ventricular ejection fraction falls when the myocardium has already lost a significant portion of its functional capacity. There are conflicting data on whether diastolic dysfunction precedes systolic dysfunction after cardiotoxic chemotherapy. We aimed to study systolic and diastolic dysfunction after cardiotoxic chemotherapy and whether diastolic dysfunction can predict subsequent risk of systolic dysfunction. It was an observational prospective cohort study, and patients receiving cardiotoxic chemotherapy were included. Baseline, demographic, and clinical details were recorded. Echocardiographic measurements of left ventricular systolic function, global longitudinal strain, and diastolic function were noted at baseline, three months, and 6 months. RESULTS: We included eighty patients. The mean age of the patients was 54.92 ± 7.6 years, predominantly females (80%). The mean left ventricular ejection fraction fell from 64.92 ± 1.96 to 60.97 ± 4.94 at 6 months. Low ejection fraction was seen in 8 (10%) patients at 6 months. The mean global longitudinal strain (GLS) at baseline was - 18.81 ± 0.797 and fell to - 17.65 ± 2.057 at 6 months, with 12 (15%) patients having low GLS (< - 18). Grade 1 diastolic dysfunction was seen in 22 (27.5%) patients, and grade 2 diastolic dysfunction was seen in 3 (3.8%) patients at 6 months. There was a significant decrease in E/A ratio (inflow early diastolic velocity/Inflow late diastolic velocity), mitral tissue Doppler velocity, and an increase in isovolumic relaxation time, mitral valve deceleration time, and E/e' (inflow early diastolic velocity/tissue Doppler mitral annular velocity), at three months and 6 months. Ejection fraction at 6 months was significantly and negatively correlated with diastolic dysfunction at three months (r = - 0.595, p = 0.02). CONCLUSIONS: Cardiotoxic chemotherapy is associated with early diastolic dysfunction. Early diastolic dysfunction predicts subsequent left ventricular systolic dysfunction.

Severe Hypertrophic Cardiomyopathy Associated With Hydroxychloroquine in a Young Woman With Systemic Lupus Erythematosus: A Case Report and Review of the Literature.

The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage, prevents disease flare, and improves overall survival. The mechanism of action of hydroxychloroquine includes interference with lysosomal degradation of cells leading to the accumulation of vacuoles. Retinopathy is a well-described adverse effect of hydroxychloroquine, thus requiring screening with an ophthalmologist after prolonged use. Although rarely reported, cardiac adverse effects of hydroxychloroquine can also occur. In this report, we present a case of a 23-year-old woman with systemic lupus erythematosus on hydroxychloroquine who presented with stroke possibly due to Libman-Sacks endocarditis and was found to have severe hypertrophic cardiomyopathy on transthoracic echocardiogram.

Myocarditis in patients on long-term antipsychotics -mechanism, management and recent updates.

Objective: Clozapine is the first atypical antipsychotic drug and was frequently cited as the most effective antipsychotic for treatment-resistant schizophrenia, but it is associated with a concert of significant cardiotoxic side effects. Clozapine-induced Myocarditis (CIM) is diagnosed based on the combination of clinical symptoms, laboratory investigations, radiological findings, and sometimes biopsy. The literature on CIM management and clinical consensus on the best course of action is mixed. Methodology: An all-language literature search on Medline, Cochrane, Embase, and Google Scholar until April 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: "CIM," "clozapine," "cardiotoxicity," and "myocarditis." We explored the literature on CIM for its pathophysiology, diagnosis, monitoring, and management. Results: The clinical features of CIM may be highly variable, ranging from asymptomatic disease to fulminant heart failure, and cessation of medication was the mainstay treatment of CIM, followed by supportive therapy. Other antipsychotics have also been linked with cardiotoxic side effects. Conclusion: Despite being the most effective antipsychotic, clozapine is associated with a cardiotoxic side effect. Current literature suggests that these antipsychotic-related cardiotoxic events impact the treatment selection for schizophrenia and other psychotic disorders, and they must be kept in mind while designing new treatment protocols in the future.

Roles of pigment epithelium-derived factor in cardiomyocytes: implications for use as a cardioprotective therapeutic.

OBJECTIVES: Cardiovascular diseases are the leading cause of death worldwide, with patients having limited options for treatment. Pigment epithelium-derived factor (PEDF) is an endogenous multifunctional protein with several mechanisms of action. Recently, PEDF has emerged as a potential cardioprotective agent in response to myocardial infarction. However, PEDF is also associated with pro-apoptotic effects, complicating its role in cardioprotection. This review summarises and compares knowledge of PEDF's activity in cardiomyocytes with other cell types and draws links between them. Following this, the review offers a novel perspective of PEDF's therapeutic potential and recommends future directions to understand the clinical potential of PEDF better. KEY FINDINGS: PEDF's mechanisms as a pro-apoptotic and pro-survival protein are not well understood, despite PEDF's implication in several physiological and pathological activities. However, recent evidence suggests that PEDF may have significant cardioprotective properties mediated by key regulators dependent on cell type and context. CONCLUSIONS: While PEDF's cardioprotective activity shares some key regulators with its apoptotic activity, cellular context and molecular features likely allow manipulation of PEDF's cellular activity, highlighting the importance of further investigation into its activities and its potential to be applied as a therapeutic to mitigate damage from a range of cardiac pathologies.

Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies.

Heart failure (HF) and cancer are the leading causes of death worldwide and accumulating evidence demonstrates that HF and cancer affect one another in a bidirectional way. Patients with HF are at increased risk for developing cancer, and HF is associated with accelerated tumour growth. The presence of malignancy may induce systemic metabolic, inflammatory, and microbial alterations resulting in impaired cardiac function. In addition to pathophysiologic mechanisms that are shared between cancer and HF, overlaps also exist between pathways required for normal cardiac physiology and for tumour growth. Therefore, these overlaps may also explain the increased risk for cardiotoxicity and HF as a result of targeted anti-cancer therapies. This review provides an overview of mechanisms involved in the bidirectional connection between HF and cancer, specifically focusing upon current 'hot-topics' in these shared mechanisms. It subsequently describes targeted anti-cancer therapies with cardiotoxic potential as a result of overlap between their anti-cancer targets and pathways required for normal cardiac function.