Direct Cardiotoxic Effects Research Articles

Hemlock (Conium Maculatum) Poisoning

Background Spotted hemlock (Conium maculatum) is one of the most poisonous plants. Hemlock poisoning is extremely rare, but can lead to serious consequences, including death.Material and methods A clinical observation of a 50-year-old patient with a diagnosis of hemlock poisoning is presented.Conclusion The clinical observation of acute hemlock poisoning presented by us does not exclude its direct cardiotoxic effect and requires further research in this direction, which will allow optimizing the treatment of this group of patients.

Cancer Therapies and Cardiomyocyte Viability: Which Drugs are Directly Cardiotoxic?

Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood. To conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability. Primary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages. We identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin [HCM viability, mean %±standard error, 13.7±3.2%], epirubicin [47.6±5.3%]), (2) antimetabolite (azacitidine [67.1±2.4%]), (3) taxanes (paclitaxel [60.2±3.0%]), (4) protein kinase inhibitors (lapatinib [49.8±7.0%], ponatinib [42.4±9.0%], pemigatinib [68.1±2.3%], sorafenib [52.9±10.6%], nilotinib [64.4±4.5%], dasatinib [38.5±3.6%]), (5) proteasome inhibitors (ixazomib citrate [65.4±7.2%]), (6) non-selective histone-deacetylase inhibitor (panobinostat [19.1±4.1%]), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib [68.2±1.7%]) and (7) vinca alkaloids (vincristine [44.6±7.4%], vinblastine [31.2±3.9%]). In total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity.

SAT342 Stress-induced Cardiomyopathy And Pheochromocytoma

Abstract Disclosure: C.G. Rivas Pajuelo: None. Introduction Pheochromocytoma (PCC) can be associated with certain genetic syndromes such as Neurofibromatosis type 1(NF1). About 5-7% of patients with NF1 will develop PCC/PGL in their lifetime. Typically, PCC presents with hypertension, and rarely, as stress-induced cardiomyopathy. Herein we present a case of a patient with NF1, and stress-induced cardiomyopathy due to Pheochromocytoma. Case presentation: A 63-year-old woman with medical history of NF1 presented to the hospital for acute hypoxemic respiratory failure and hypertensive emergency. On admission, had troponin level 27 ng/L, pro-BNP 2446 pg/ml; had a transthoracic echocardiogram (TTE) that showed EF of 30%, with global hypokinesis, anteroseptal and inferoseptal akinesis. Given NF1 history and hypertension, a CT chest/abdomen/pelvis was ordered and showed bilateral adrenal adenomas; a 2.6 cm left adrenal adenoma HFU 3, and a right adrenal mass 4.0 x 3.7 cm HFU 45 with indeterminate density. Biochemically, had markedly elevated plasma catecholamines (epinephrine 352 pg/mL, Norepinephrine 1904 pg/mL) and urinary metanephrines (2155 mcg/24 h). She markedly improved after IV diuresis, and prior to discharge was started on alpha-blockade with prazosin. This was titrated as outpatient, with addition of metoprolol 1 week later. MIBG showed intense tracer uptake in the right adrenal gland suggestive of pheochromocytoma, the left adrenal nodule was lipid rich. A repeat TTE 2 months later showed improved EF to 60% and had left heart catheterization revealing normal coronary arteries. She underwent right laparoscopic adrenalectomy, with final pathology report of 4.8 cm pheochromocytoma with negative margins. Discussion: Stress-induced cardiomyopathy is a life-threatening complication that can be the initial presentation in patients with PCC. Hypersecretion of catecholamines specifically norepinephrine and epinephrine, are thought to play a role in combination with PCC tumor cells, to act synergistically and induce direct cardiotoxic effect. Treatment with medical management followed by surgical excision of the PCC will reverse cardiomyopathy as in our patient. Ultimately, because patients with NF1 are at increased risk for PCC, it is recommended they undergo screening with plasma metanephrines and catecholamines or urinary metanephrines at least every 1-2 years especially if hypertension or tachycardia are present. Presentation: Saturday, June 17, 2023

PSAT051 Posterior Reversible Leukoencephalopathy Syndrome Associated With Cushing's Syndrome

Abstract Background Corticosteroids can induce hypertension through a variety of mechanisms such as vasoconstriction, increased hepatic production of angiotensinogen, sympathetic activity, and possible direct cardiotoxic effect. Posterior reversible leukoencephalopathy syndrome (PRES), a syndrome with unclear pathogenesis, can be the consequence of blood pressure elevation in these patients, which can present with headaches, altered consciousness, visual disturbances, or seizures. CASE REPORTA 57-year-old African American woman with a history of hypertension on Lisinopril 40mg as an outpatient, who was brought to the emergency department (ED) by family members due to altered mental status (AMS). Daughter reports that a day prior to the admission the patient has complained of feeling unwell, with mild shortness of breath and anxiety. On admission, she was found to be on sinus tachycardia with heart rate between 100-140bpm and severely hypertensive at 203/107mmHg. Toxicology screen was positive for cannabinoids, which the patient admitted to vapping the night prior. At the ED, Stroke alert was called due to altered mentation and weakness, however CT brain showed no large infarct or hemorrhage. MRI was obtained and showed patchy t2/flair hyperintense signal abnormality predominantly of the subcortical white matter in the bilateral frontoparietal lobes, most conspicuous at the vertex. Findings could reflect acute hypertensive encephalopathy (PRES). The patient had a Cushingoid appearance, with truncal obesity, moon face and reported easy bruising. Given the clinical findings and severe hypertension, serum cortisol was obtained at night and was found to be elevated at 34. 08UG/DL (3.44 - 16.76 ug/dl). ACTH was mildly low at 5 pg/mL (6-50pg/mL). 24-hour urine cortisol was then ordered and also found to be elevated at 818mcg/24h (4-50mcg/24h). Blood pressure was controlled with antihypertensive medications (nifedipine 60mg and carvedilol 12.5mg), AMS resolved and patient was discharged home with follow up with endocrinology for further Cushing's workup. Conclusion Cushing Syndrome is a known cause of secondary hypertension that should not be neglected. Patients that present with severe or resistant hypertension regardless of age should be worked up for possible secondary cases. Patients with Cushing syndrome are at elevated cardiovascular risk and the sooner the diagnosis is made, the better, so they can receive appropriate treatment. Hypertensive crisis can present as PRES syndrome and patients with clinical suspicion for Cushing should be worked up for the condition. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Cellular and Molecular Mechanisms of MEK1 Inhibitor–Induced Cardiotoxicity

BackgroundTrametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)–mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized. ObjectivesThe aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function. MethodsMice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery. ResultsLong-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment. ConclusionsThese data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.

Особенности течения острого коронарного синдрома у пациентов с новой коронавирусной инфекцией COVID-19

INTRODUCTION: Coronary heart disease (CHD) is an important medical and social problem. It occupies one of the leading positions in the structure of morbidity, temporary and permanent disability and mortality. The peculiarities of the course of acute coronary syndrome (ACS) in patients with new coronavirus infection COVID-19 are of great clinical interest. Studies have shown that the effect of COVID-19 on the cardiovascular system consists not only the in direct cardiotoxic effect of the virus, but also in myocardial damage due to hemodynamic disorders, systemic hypoxia, destabilization of atherosclerotic plaques due to endothelial dysfunction, increased myocardial oxygen demand as a response to systemic inflammation, coagulopathy and others. An important role is played by the involvement of the vascular endothelium in the pathological process. There is extensive evidence of SARS-CoV-2 directly infecting endothelial cells because of the high level of expression of angiotensin-converting enzyme 2. The combination of ACS and new coronavirus infection is a frequent event in both infectious disease units and specialized coronary centers. However, many questions of pathogenesis, clinical presentation, diagnosis and management tactics of such patients are not clear enough. There are data on the manifestation of cardiovascular diseases against the background COVID-19. The difficulty is that clinical presentation of acute coronary syndrome in COVID-19 patients can be masked by peculiarities of the course of infectious disease itself. CONCLUSION: Differential diagnosis of COVID-19 and ACS has also become a problem for clinicians due to the fact that symptoms of chest pain or chest tightness are common in patients with new coronavirus infection. Myocardial damage in coronavirus infection can impair interpretation of the results of some clinical diagnostic tools. A complex disputable problem is assessment of prognosis in ACS combined with COVID-19. Most patients with COVID-19 have disorders of the clotting system, the severity of which determines the probability of adverse outcomes, above all, the risk of death.

Yohimbine Directly Induces Cardiotoxicity on Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Yohimbine is a highly selective and potent α2-adrenoceptor antagonist, which is usually treated as an adjunction for impotence, as well for weight loss and natural bodybuilding aids. However, it was recently reported that Yohimbine causes myocardial injury and controversial results were reported in the setting of cardiac diseases. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to explore electrophysiologic characterization after exposure to Yohimbine. HiPSC-CMs were differentiated by employment of inhibitory Wnt compounds. For analysis of electrophysiological properties, conventional whole-cell patch-clamp recording was used. Specifically, spontaneous action potentials, pacemaker currents (If), sodium (Na+) channel (INa), and calcium (Ca++) channel currents (ICa) were assessed in hiPSC-CMs after exposure to Yohimbine. HiPSC-CMs expressed sarcomeric-α-actinin and MLC2V proteins, as well as exhibited ventricular-like spontaneous action potential waveform. Yohimbine inhibited frequency of hiPSC-CMs spontaneous action potentials and significantly prolonged action potential duration in a dose-dependent manner. In addition, rest potential, threshold potential, amplitude, and maximal diastolic potential were decreased, whereas APD50/APD90 was prolonged. Yohimbine inhibited the amplitude of INa in low doses (IC50 = 14.2μM, n = 5) and inhibited ICa in high doses (IC50 = 139.7μM, n = 5). Whereas Yohimbine did not affect the activation curves, treatment resulted in left shifts in inactivation curves of both Na+ and Ca++ channels. Here, we show that Yohimbine induces direct cardiotoxic effects on spontaneous action potentials of INa and ICa in hiPSC-CMs. Importantly, these effects were not mediated by α2-adrenoceptor signaling. Our results strongly suggest that Yohimbine directly and negatively affects electrophysiological properties of human cardiomyocytes. These findings are highly relevant for potential application of Yohimbine in patients with atrioventricular conduction disorder.

Fisetin ameliorates ischemia re-oxygenation injury in H9c2 cardiomyocytes via targeting the PI3K signalling pathway

BackgroundThe rat myocardium consists of different cell types of which cardiomyocytes account for 70% of the total surface area. The extent of ischemia reoxygenation injury (IRI) experienced by each cell type of the heart varies. Fisetin, a natural flavonoid is reported to ameliorate reperfusion injury in rat heart but the direct cardiotoxic effect of fisetin and its impact on IRI is yet to be evaluated in rat cardiomyocytes. PurposeTo evaluate the impact of IRI in cardiomyocytes and to study the underlying mechanism. MethodsIn the present study, to mimic myocardial ischemia reperfusion, ischemia re-oxygenation (IR) model was adopted in H9c2 (2-1) cells. Fisetin (20 µM) was administrated to the cells: before ischemia, during ischemia and after ischemia via the respective incubation medium. ResultsThe results showed that fisetin pre-treatment renders significant improvement in cell viability in IR simulated cells when compared with other two modes of administration. In addition, fisetin significantly reduced oxidative stress and improved mitochondrial ETC enzyme activity. However, the fisetin-mediated protection was absent in presence of rotenone. Fisetin pre-treatment enhanced the activation of PI3K pathway in IR simulated cells, which was further reconfirmed using Wortmannin, a PI3K inhibitor, where the protective effect of fisetin was negated. ConclusionFisetin pre-treatment increases cell viability via reducing oxidative stress and preserving the functional activity of mitochondria in H9c2 cells. The underlying mechanism of action is associated with the activation of the PI3K signalling pathway.

Intestinal Microbial-tissue Complex and Chronic Heart Failure (part 1): Pathogenesis

Antigenic and metabolic integration of the intestinal microbiota into the homeostasis of the human body is a factor that claims to play a key role in the pathogenesis of cardiovascular diseases. It acquires special significance against the background of the decrease in blood circulation and congestion in the digestive system during chronic heart failure. Aim of the review is analysis and synthesis of studies results on the role of intestinal microbiocenosis in the pathogenesis of heart remodeling and chronic heart failure. The search for articles was conducted in databases eLIBRARY.RU and Medline for the key terms "gut microbiota (microbiome, microbiocenosis)", "dysbiosis (dysbacteriosis)", "excessive bacterial growth syndrome", "lipopolysaccharide (endotoxin)", "trimethylamine-N-oxide" in combination with the terms "heart failure", "myocardial remodeling", "myocardium" in Russian and English, respectively. We selected articles containing the results of clinical and experimental studies published from 1995 to 2020. Review articles were considered only on the subject of the cited original publications. Most researchers have established the relationship between chronic heart failure and dysfunction and changes in the qualitative and quantitative composition of intestinal microbiocenosis. As negative changes, it is customary to note the proliferation of gram-negative opportunistic bacteria with concomitant endotoxinemia and a decrease in the pool of commensal microbiota. The available data suggest that the participation of the intestinal microbial-tissue complex in the pathogenesis of chronic heart failure and heart remodeling is realized through the activation of a local and then systemic inflammatory response, accompanied by cardiodepressive action of pro-inflammatory cytokines and universal proliferation factors, an imbalance of matrix metalloproteinases and their inhibitors, the initiation of apoptosis, fibrosis, and loss of contractile myocardium. Besides, a decrease in the production of short-chain and polyunsaturated fatty acids and vitamins by the commensal microbiota may be associated with changes in the electrical properties of cardiomyocyte membranes, a decrease in the systolic function of the left ventricle of the heart, and an increase in the risk of sudden cardiac death. It's also shown that the direct cardiotoxic effect of microbial molecules (lipopolysaccharides, peptidoglycans, trimethylamine-N-oxide, etc.), which interact with the receptors of cardiomyocytes and microenvironment cells, can cause the development of myocardial remodeling and its dysfunction. Recent studies have established mechanisms of myocardial remodeling mediated by microbial molecules, which may be associated with new strategies for the treatment and prevention of heart failure.

SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function.

SummaryCOVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2.

Abstract 15362: Epicardial Adipose Tissue Effects on Systolic Function: A Direct or Systemic Metabolic Effect?

Introduction: Obesity is associated with increased epicardial adipose tissue (EAT). It is unknown if this ectopic fat deposit has direct cardiotoxic paracrine effects on regional systolic function. We have previously shown that EAT mediates diastolic dysfunction via systemic effects, rather than localized effects. We similarly hypothesized regional EAT deposits would have no effect on the left ventricular (LV) strain of adjoining myocardial segments. Methods: We studied 28 obese healthy adults (mean age 48 ± 5 yrs, BMI 38.2 ± 5.0 kg/m 2 ). EAT was quantified on each individual MRI slice from base to apex and summed to obtain total volume. It was then separated into anterior, lateral, and inferior regions corresponding to the adjacent LV segments. Using MRI feature tracking, global longitudinal LV strain (GLS) and peak regional anterior, inferior, and lateral LV strain were quantified. Associations between total EAT and GLS, and between regional EAT and corresponding regional strain were determined by linear regression. Results: Mean total EAT volume was 69.6 ± 29.8 mL and mean GLS was -19.4 ± 2.0%. Individual data points for EAT and longitudinal strain are shown in the figure. Greater total EAT volume was modestly associated with decreased GLS (r2 = 0.127). However, anterior, lateral, and inferior EAT volume did not correlate with a decrease in corresponding regional strain (r2 = 0.003, r2 = 0.088, r2 = 0.016, respectively). Conclusion: In obese adults, total EAT volume was associated with a decrease in global LV systolic function measured by GLS. There was no association between regional EAT depots and corresponding regional LV function to suggest localized metabolic cardiotoxic effect. These preliminary results support our previous findings that EAT has little paracrine effect on cardiac function. Rather, EAT likely represents an additional depot of ectopic fat reflective of a general metabolic abnormality.

Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus

Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus

Cardiovascular Consequences of Skeletal Muscle Impairments in Breast Cancer.

Breast cancer survivors suffer from disproportionate cardiovascular disease risk compared to age-matched controls. Beyond direct cardiotoxic effects due to treatments such as chemotherapy and radiation, breast-cancer-related reductions in skeletal muscle mass, quality and oxidative capacity may further contribute to cardiovascular disease risk in this population by limiting the ability to engage in aerobic exercise—a known promoter of cardiovascular health. Indeed, 20–30% decreases in peak oxygen consumption are commonly observed in breast cancer survivors, which are indicative of exercise intolerance. Thus, breast-cancer-related skeletal muscle damage may reduce exercise-based opportunities for cardiovascular disease risk reduction. Resistance training is a potential strategy to improve skeletal muscle health in this population, which in turn may enhance the capacity to engage in aerobic exercise and reduce cardiovascular disease risk.

Right ventricular 2D speckle-tracking echocardiography in children with osteosarcoma under chemotherapy

BackgroundCardiotoxicity from anthracyclin chemotherapy is a leading cause of death in patients with cancer. Therefore, left ventricular (LV) function is routinely assessed during protocol to detect cardiotoxicity; however, animal studies suggest that right ventricular (RV) function may be also impaired. So, our objective was to investigate the incidence of RV dysfunction in children with osteosarcoma receiving anthracyclines and to highlight the role of 2D STE in early detection of RV dysfunction.ResultsRV function was affected by anthacyclines through direct cardiotoxic effect on RV myocardium without simultaneous derangement of LV function. Furthermore, there is a direct proportion between the incidence of RV dysfunction and the cumulative dose of anthracyclines. At the first echo follow-up at 10th week, 7 patients had impaired RV GLS in comparison to baseline study. At 20th week, the number of patients with impaired RV strain increased to 10. At 29th week, it reaches 12 patients. This effect was early detected by RV 2DSTE before adversely affecting TAPSE and FAC. The incidence of RV dysfunction from anthracyclines was around 12%, and the recovery rate was around 8% in 3 months after completion of chemotherapy.ConclusionRV 2DSTE is the best modality to detect early affection of RV function in comparison with other modalities. RV function decreases early even before derangement of LV function. Accordingly, it should be assessed separately in all patients who received anthracyclines even without evident LV affection.

Microvascular Endothelial Function across the Cancer Survivorship Continuum

BackgroundChemotherapy for the treatment of various cancers has previously been shown to have direct cardiotoxic effects. However, changes in endothelial function due to chemotherapy‐induced toxicity in cancer survivors during the years following treatment remains poorly understood. Therefore, the purpose of this study was to evaluate microvascular endothelial‐dependent vasodilation across the cancer survivorship continuum as well as in healthy controls. We hypothesized that early cancer survivors would yield a decreased percent change in skin blood flow and cutaneous vascular conductance when compared to late survivors and controls.MethodsTo date, thirteen female cancer survivors and thirteen healthy controls (cancer free with no history of chemotherapy) participated in this study. Of the cancer survivors nine were defined as early survivors (within 5 years of chemotherapy treatment) and four as late survivors (> 5 years post chemotherapy treatment). Skin blood flow (SkBF) was measured via integrated laser Doppler flowmetry. Mean arterial pressure (MAP) was measured and used to calculate cutaneous vascular conductance (CVC = SkBF/MAP *100). Endothelium‐dependent cutaneous microvascular function was determined as the percent change in SkBF and CVC in response to iontophoresis of 2% acetylcholine (ACh).ResultsThere were no differences in age between groups (early vs. late: P=0.8; late vs. control: P=0.7; early vs. control: P=0.8). The hyperemic responses for SkBF (early: 1081 ± 718% Δ; late: 1458 ± 653% Δ; P=0.4) and CVC (early: 1060 ± 694% Δ; late: 1499± 751% Δ; P=0.5) were not significantly different between early and late cancer survivors. Similarly, the SkBF (early: 1081 ± 718% Δ; control: 1554 ± 655% Δ; P=0.3) and CVC (early: 1060 ± 694% Δ; control: 1472 ± 626% Δ; P=0.1) were not significantly different in the early cancer survivors compared to controls. There was no significant difference in SkBF (late: 1458 ± 653% Δ; control: 1554 ± 655% Δ; P=0.8) and CVC (late: 1499± 751% Δ; control: 1472 ± 626% Δ; P=0.9) between late cancer survivors and controls.ConclusionEndothelium‐dependent cutaneous microvascular function is not different between early cancer survivors compared to those >5 years post‐chemotherapy and healthy controls. These results suggest that microvascular endothelial function is restored in the early years following chemotherapy and is maintained in later years of survivorship. Additional work is required to determine if endothelial dysfunction occurs in other important vascular beds.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PTH, vitamin D, and the FGF-23-klotho axis and heart: Going beyond the confines of nephrology.

Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart. The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting. Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF-23-klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF-23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation. Among all mineral components, an increase in systemic FGF-23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF-23, especially those related to cardiomyocyte function, remain to be discovered.

Abstract 11217: Association of Hepatitis C infection and Incident Atrial Fibrillation

Introduction: Prior studies have shown that HIV infection is associated with incident atrial fibrillation (AF). Anecdotal evidence suggests that patients with Hepatitis C virus (HCV) infection may also be at increased risk of AF at a young age. Hypothesis: We postulate that HCV infection increases the risk of incident AF. Methods: We performed a case-control study using administration data from the Veterans Health Administration. ‘Case’ patients included 103876 VA patients newly diagnosed with HCV during 2005-2013; patients with no use of VA services during the year prior to HCV diagnosis and patients with pre-existing AF were excluded. Each ‘case’ patient was matched to a single patient without HCV or AF. Patients were matched by age, race, gender, prior use of VA services, hypertension, sleep apnea, and other AF risk factors. Cox proportional hazards regression was used to define the association between HCV infection and incident AF. Results: The HCV and control groups were well matched by demographics and co-morbidities. The average follow-up period was 4.3 years. Among patients with HCV, 4087 (3.9%) patients were diagnosed with incident AF; 3185 (3.1%) patients without HCV were diagnosed with incident AF. Overall, the rate of new AF diagnosis per 10 patient-years of follow-up was 9.7% and 6.8% for patients with and without HCV, respectively. In Cox proportional hazards regression models, the relative hazard of AF was 1.42 times higher (95% CI, 1.35-1.48; p<0.001) for patients with HCV compared to those without. Conclusions: HCV infection appears to be associated with an increased risk of developing AF. Possible mechanisms include chronic systemic inflammation associated with HCV infection or direct cardiotoxic effects of the virus. It is unknown whether the use of new curative medications to eradicate HCV will reduce the incident risk of AF in these patients.

Evaluation of the Colchicine Poisoning Cases in a Pediatric Intensive Care Unit: Five Year Study

BackgroundColchicine poisoning is an uncommon but serious form of drug intoxication. It may produce life-threatening systemic effects. In toxic doses it produces nausea and vomiting and bone marrow suppression, often leading to sepsis, hypocalcemia, adult respiratory distress syndrome, and direct cardiotoxic effects. ObjectiveThe aim of this study was to describe demographic features and the outcome of patients poisoned with colchicine. MethodsA retrospective study of the pediatric intensive care unit database was performed for patients ≤18 years of age who had colchicine poisoning between July 2008 and July 2013. ResultsThe total number of patients with drug poisoning in the study period was 144. Nine of 144 were related to colchicine poisoning. The median age was 4 years (range 20 months to 16 years) and the number of females was five. Six of the nine cases presented after ingesting <0.5 mg/kg, whereas two patients had consumed 0.5 to 0.8 mg/kg. One patient had received colchicine >0.8 mg/kg. Three patients died. ConclusionsAmong drug intoxications, colchicines can lead to severe clinical conditions. All patients suspected of having colchicine intoxication should be managed in the pediatric intensive care unit regardless of the actual degree of poisoning.

A study on paracetamol cardiotoxicity.

BackgroundSri Lanka has a high suicide rate, with more than 40 % of poisoning admissions due to overdose of drugs with Paracetamol being the commonest. Data regarding cardiotoxicity to paracetamol is very minimal though hepatotoxicity following poisoning is well studied. Paracetamol cardiotoxicity has rarely been clinically significant and may have well been overlooked. The possibility that paracetamol overdose might be directly cardiotoxic has been the subject of a few reports. Unexplained deaths and electrocardiographic changes associated with paracetamol poisoning have also been reported in which cardiac origin cannot be clearly ruled out. Although some studies state that paracetamol poisoning has no direct cardiotoxic effect, electrocardiographic changes due to metabolic derangement of hepatotoxicity have been shown in certain studies. Thus, we conducted this study to assess in detail the cardiotoxic effect of paracetamol poisoning.MethodsThis is a cross sectional descriptive study done on those with confirmed paracetamol poisoning. Serum paracetamol levels, Electrocardiogram, Echocardiogram, troponin I, and other basic investigations were done.ResultsParacetamol ingestion is more common among teenagers and the young population in Sri Lanka. Although several cases of paracetamol poisoning induced cardiotoxicity has been described in the past, this study demonstrated no electrocardiographic, echocardiographic or cardiac biomarkers changes of myocardial toxicity.ConclusionThough literature review support cardiotoxicity following paracetamol poisoning, our study does not provide enough evidence for this. Continuous cardiac monitoring, serial troponin and echocaediogram assessment would be voluble adjunct in its management. Further experiments and research in this subject would be useful with a larger number of samples to further evaluate this important problem.

Characterization of Atrial Fibrillation and Bleeding Risk Factors in Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Retrospective Cohort Study of Administrative Medical Claims Data in the United States (US)

Background:CLL is the most common form of adult leukemia in the Western World. It primarily affects the elderly with ~70% of patients diagnosed ≥65 years of age. Therapy is reserved until symptoms occur, when most patients have multiple chronic comorbidities including hypertension, arrhythmias, and other conditions that require the use of anticoagulants and/or antiplatelet agents. Understanding the frequency of use of these agents and bleeding events in routine clinical practice could provide additional insights on the real-world burden of the use of these drugs in patients with an underlying predisposition to bleeding due to CLL-related thrombocytopenia and other comorbidities. This is particularly relevant as several chemoimmunotherapy regimens used in CLL may have direct cardiotoxic and antiplatelet effects. Most importantly, emerging evidence suggests that some of the recently approved targeted agents may be associated with risk of cardiac arrhythmias or bleeding events. The mechanisms behind these events and the relations between them are largely unclear but affect the quality of life of CLL patients. The aim of this retrospective database study was to characterize the outcomes of newly diagnosed CLL patients in terms of: [1] incidence of atrial fibrillation (AFIB), [2] incidence of AFIB risk factors, [3] bleeding risk factors as measured by the 5-variable Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score (which quantifies the risk of drug-associated hemorrhage), and [4] anticoagulant/antiplatelet drug usage over the course of their treatment.Methods:Based on administrative medical claims from the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases in the US, we identified adults diagnosed with CLL between 1/1/2004 - 4/30/2015. Patients selected for this study were required to have at least two treatment lines where the 2nd line treatment represented a change in initial therapy (index date = start of 1st line treatment). anticoagulant/antiplatelet use, incidence of AFIB (per 10,000 patient days), and ATRIA bleeding risk score were assessed during 1st and 2nd line treatment. Patients were continuously enrolled for ≥ 6 months (baseline) before index date, and followed until disenrollment from the health plan or 4/30/2015, whichever came first.Results:Of approximately 67 million adults (per year) in the database, we identified 2,335 adults with newly diagnosed CLL (mean age: 62 years; 66% male; 46% Medicare as primary payer) treated with antineoplastic therapy and followed for a mean of 35.3 months. The mean duration of first line treatment was 3.3 months, and 4.1 months for 2nd line treatment. Anticoagulant/antiplatelet use at baseline was common (25%), and use increased during 1st line (31%) and 2nd line (32%) treatment. During follow-up, the incidence of AFIB during 1st line and 2nd line treatment was 4.57 and 5.70/10,000 person days (95% CI: 3.7-5.5 and 4.8-6.6), respectively. The proportion of patients with ATRIA scores indicating moderate (ATRIA score 4) to high (ATRIA score ≥ 5) risk of bleeding increased from initial therapy (1st line treatment = 18%) to salvage therapy (2nd line treatment = 22%) [see Figure].Conclusions:We provide the first real-world estimates of anticoagulant/antiplatelet use, AFIB, AFIB risk, and bleeding risk factors in adult patients newly diagnosed with CLL in the US. In our study, the use of anticoagulant/antiplatelet agents at diagnosis was common (25%) and increased over time from 1st to 2nd line treatment. Similarly, AFIB incidence and the ATRIA bleeding risk score also increased over the course of the natural disease progression. Since ATRIA scores of ≥ 5 correlate with a 5.8% annual risk of major hemorrhage, understanding the characteristics of the CLL patients at diagnosis and relapse will ultimately help optimize treatment selection based on the potential risks and benefits of each individual treatment regimen. These data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CLL. [Display omitted] DisclosuresBarrientos:Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Meyer:Truven Health Analytics: Employment. Song:Truven Health Analytics: Employment. Rai:Leon Levy Foundation: Research Funding; Nash Family Foundation: Research Funding; Nancy Marks Family Foundation: Research Funding; Karches Family Foundation: Research Funding.