cardiovascular-agents and Cardiotoxicity

Manifestations of cardiovascular diseases (CVDs) in a patient or a population differ based on inherent biological makeup, lifestyle, and exposure to environmental risk factors. These variables mean that therapeutic interventions may not provide the same benefit to every patient. In the context of CVDs, human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an opportunity to model CVDs in a patient-specific manner. From a pharmacological perspective, iPSC-CM models can serve as go/no-go tests to evaluate drug safety. To develop personalized therapies for early diagnosis and treatment, human-relevant disease models are essential. Hence, to implement and leverage the utility of iPSC-CMs for large-scale treatment or drug discovery, it is critical to (i) carefully evaluate the relevant limitations of iPSC-CM differentiations, (ii) establish quality standards for defining the state of cell maturity, and (iii) employ techniques that allow scalability and throughput with minimal batch-to-batch variability. In this review, we briefly describe progress made with iPSC-CMs in disease modelling and pharmacological testing, as well as current iPSC-CM maturation techniques. Finally, we discuss current platforms for large-scale manufacturing of iPSC-CMs that will enable high-throughput drug screening applications.

Topics: Biomedical Research; Cardiology; Cardiotoxicity; Cardiovascular Agents; Cardiovascular Diseases; Cell Culture Techniques, Three Dimensional; Cell Differentiation; Cell Proliferation; Clinical Decision-Making; Drug Discovery; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Phenotype; Risk Assessment; Toxicity Tests

Cardiotoxicity, defined as toxicity that affects the heart, is one of the most common adverse drug effects. Numerous drugs have been shown to have the potential to induce lethal arrhythmias by affecting cardiac electrophysiology, which is the focus of current preclinical testing. However, a substantial number of drugs can also affect cardiac function beyond electrophysiology. Within this broader sense of cardiotoxicity, this review discusses the key drug-protein interactions known to be involved in cardiotoxic drug response. We cover adverse effects of anticancer, central nervous system, genitourinary system, gastrointestinal, antihistaminic, anti-inflammatory, and anti-infective agents, illustrating that many share mechanisms of cardiotoxicity, including contractility, mitochondrial function, and cellular signaling.

Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Arrhythmias, Cardiac; Cardiotoxicity; Cardiovascular Agents; Drug Development; Gastrointestinal Agents; Genitourinary Agents; Histamine Antagonists; Humans; Mitochondria, Heart; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Neuroprotective Agents; Safety-Based Drug Withdrawals; Signal Transduction

Cardiovascular (CV) disease and cancer are the leading causes of death.1,2 Over the last decades, it has been appreciated that both CV disease and cancer are more common in individuals in whom risk factors for disease development accumulate, and preventative measures have been extremely important in driving down the incidence of disease.3-6 In general, the field of epidemiology, risk reduction, and preventative trials is divided into health care professionals who have an interest in either CV disease or cancer. As a result, the medical literature and medical practice has largely focused on the one disease, or the other. However, human individuals do not behave according to this dogma. Emerging data clearly suggest that identical risk factors may lead to CV disease in the one individual, but may cause cancer in another, or even both diseases in the same individual. This overlap exists between risk factors that are historically classified as 'CV risk factors' as these factors do equally strong predict cancer development. Therefore, we propose that a holistic approach might better estimate actual risks for CV disease and cancer. In this review, we summarize current insights in common behavioural risk factors for heart failure, being the most progressed and lethal form of CV disease, and cancer.

Topics: Antineoplastic Agents; Cardiotoxicity; Cardiovascular Agents; Heart Failure; Humans; Neoplasms; Prognosis; Risk Assessment; Risk Factors

Cardiomyocytes derived from human pluripotent stem cells (hPSCs) are emerging as an invaluable alternative to primarily sourced cardiomyocytes. The potentially unlimited number of hPSC-derived cardiomyocytes (hPSC-CMs) that may be obtained in vitro facilitates high-throughput applications like cell transplantation for myocardial repair, cardiotoxicity testing during drug development, and patient-specific disease modeling. Despite promising progress in these areas, a major disadvantage that limits the use of hPSC-CMs is their immaturity. Improvements to the maturity of hPSC-CMs are necessary to capture physiologically relevant responses. Herein, we review and discuss the different maturation strategies undertaken by others to improve the morphology, contractility, electrophysiology, and metabolism of these derived cardiomyocytes.

Topics: Animals; Cardiotoxicity; Cardiovascular Agents; Cell Differentiation; Cell Lineage; Cells, Cultured; Drug Discovery; Humans; Myocytes, Cardiac; Phenotype; Pluripotent Stem Cells; Stem Cell Transplantation; Toxicity Tests

The advent of biologic therapy has enhanced our ability to augment disease in an increasingly targeted manner. The use of biologics in cardiovascular disease (CVD) has steadily increased over the past several decades. Much of the early data on biologics and CVD were derived from their use in rheumatologic populations. Atherosclerosis, myocardial infarction, and heart failure have been closely linked to the inflammatory response. Accordingly, cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 have been targeted. Noninflammatory mediators, such as proprotein convertase subtilisin kexin type 9 (PCSK9), have been selected for therapeutic intervention as well. Furthermore, RNA interference (RNAi) therapy has emerged and may serve as another targeted therapeutic mechanism. Herein, we will review the history, obstacles, and advances in using biologic therapy for CVD.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Cardiotoxicity; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Humans; Inflammation Mediators; Liposomes; Proprotein Convertase 9; RNA, Small Interfering; RNAi Therapeutics; Signal Transduction; Treatment Outcome

In recent decades, cardiovascular diseases have become the greatest health threat to human beings, and thus it is particularly important to explore the subtle underlying pathogenesis of cardiovascular diseases. Although many molecular pathways have been explored to be essential in the development of cardiovascular diseases, their clinical significances are still uncertain. With the emergence of induced pluripotent stem cells (iPSCs), a unique platform for cardiovascular diseases has been established to model cardiovascular diseases on specific genetic background in vitro. This review summarizes current progresses of iPSCs in cardiovascular disease modeling and drug testing. This review highlighted iPSC-based cardiovascular disease modeling and drug testing. The technical advances in iPSC-based researches and various clinically relevant applications are discussed. With further intensive research, iPSC technology will shape the future of clinical translational research in cardiovascular diseases.

Topics: Animals; Cardiotoxicity; Cardiovascular Agents; Cells, Cultured; Drug Discovery; Genotype; Heart Diseases; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Phenotype; Toxicity Tests

Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways. Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane. New treatments exploiting the ErbB or other novel pro-survival pathways, such as conditioning, are on the cardioprotection horizon. Even in the forthcoming era of targeted cancer therapies, the substantial proportion of today's anthracycline-treated cancer patients may become tomorrow's cardiac patient.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Cardiovascular Agents; Cytoprotection; Heart Diseases; Humans; Myocytes, Cardiac; Risk Factors; Signal Transduction; Time Factors; Troponin

Cardiac toxicity represents one of the leading causes of drug failure along different stages of drug development. Multiple very successful pharmaceuticals had to be pulled from the market or labeled with strict usage warnings due to adverse cardiac effects. In order to protect clinical trial participants and patients, the International Conference on Harmonization published guidelines to recommend that all new drugs to be tested preclinically for hERG (Kv11.1) channel sensitivity before submitting for regulatory reviews. However, extensive studies have demonstrated that measurement of hERG activity has limitations due to the multiple molecular targets of drug compound through which it may mitigate or abolish a potential arrhythmia, and therefore, a model measuring multiple ion channel effects is likely to be more predictive. Several phenotypic rapid-throughput methods have been developed to predict the potential cardiac toxic compounds in the early stages of drug development using embryonic stem cells- or human induced pluripotent stem cell-derived cardiomyocytes. These rapid-throughput methods include microelectrode array-based field potential assay, impedance-based or Ca(2+) dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.

Topics: Action Potentials; Animals; Cardiotoxicity; Cardiovascular Agents; Cells, Cultured; Drug Evaluation, Preclinical; Embryonic Stem Cells; ERG1 Potassium Channel; High-Throughput Screening Assays; Humans; Induced Pluripotent Stem Cells; Microelectrodes; Myocytes, Cardiac; Safety-Based Drug Withdrawals

Anthracyclines (ANTs) are a class of active antineoplastic agents with topoisomerase-interacting activity that are considered the most active agents for the treatment of breast cancer. We investigated the efficacy of carvedilol in the inhibition of ANT-induced cardiotoxicity.. In this randomized, single-blind, placebo-controlled study, 91 women with recently diagnosed breast cancer undergoing ANT therapy were randomly assigned to groups treated with either carvedilol (n = 46) or placebo (n = 45). Echocardiography was performed before and at 6 months after randomization, and absolute changes in the mean left ventricular ejection fraction, left ventricular end diastolic volume, and left ventricular end systolic volume were determined. Furthermore, the percentage change in the left atrial (LA) diameter and other variables of left ventricular (LV) diastolic function, such as transmitral Doppler parameters, including early (E wave) and late (A wave) diastolic velocities, E/A ratio and E wave deceleration time, pulmonary venous Doppler signals, including forward systolic (S wave) and diastolic (D wave) velocities into LA, late diastolic atrial reversal velocity, and early diastolic tissue Doppler mitral annular velocity (e') were measured. In addition, tissue Doppler mitral annular systolic (s') velocity, as a marker of early stage of LV systolic dysfunction, E/e' ratio, as a determinant of LV filling pressure, and troponin I level, as a marker of myocardial necrosis were measured.. At the end of follow-up period, left ventricular ejection fraction did not change in the carvedilol group. However, this parameter was significantly reduced in the control group (P < 0.001). Echocardiography showed that both left ventricular end systolic volume and LA diameter were significantly increased compared with the baseline measures in the control group. In pulse Doppler studies, pulmonary venous peak atrial reversal flow velocity was significantly increased in the control group. Moreover, a significant decrease in the mitral annuli early diastolic (e') and peak systolic (s') velocities and a significant increase in the E (the peak early diastolic velocity)/e' ratio in the control group were also observed. However, none of these variables were adversely changed at the end of follow-up in the carvedilol group. Furthermore, the TnI level was significantly higher in the control group than in the carvedilol group (P = 0.036) at 30 days after the initiation of chemotherapy.. Prophylactic use of carvedilol may inhibit the development of anthracycline-induced cardiotoxicity, even at low doses.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Atrial Function, Left; Biomarkers; Breast Neoplasms; Carbazoles; Cardiotoxicity; Cardiovascular Agents; Carvedilol; Echocardiography, Doppler, Pulsed; Female; Heart Diseases; Humans; Iran; Middle Aged; Propanolamines; Risk Assessment; Risk Factors; Single-Blind Method; Stroke Volume; Time Factors; Treatment Outcome; Troponin I; Ventricular Function, Left; Young Adult

Drug-induced cardiotoxicity is a potentially severe side effect that can alter the contractility and electrophysiology of the cardiomyocytes. Cardiotoxicity is generally assessed through animal models using conventional drug screening platforms. Despite significant developments in drug screening platforms, the difficulty in measuring electrophysiology and contractile profile together affects the investigation of cardiotoxicity in potential drugs. Some drugs can prove to be more toxic to contractility than electrophysiology, which demands the need for a reliable, dual, and simultaneous drug screening platform. Herein, we propose the microelectrode array integrated SU-8 cantilever for dual and simultaneous measurement of electrophysiology and contractility of cardiomyocytes. The SU-8 cantilever is integrated with microelectrode array (C-MEA) using conventional photolithographic techniques. Drug tests are conducted to verify the feasibility of the C-MEA platform using three cardiovascular drugs. Clinically recognized drugs, quinidine and verapamil, are used to activate both the hERG channel and the contractile characteristics of cardiomyocytes. The effect of ion channel blockers on the field potential duration (FPD) of the cardiomyocytes is compared with several contractility-based parameters. The contraction-relaxation duration (CRD) profile is relatively close to that of FPD in tested drugs (half-maximal (IC

Topics: Animals; Biosensing Techniques; Cardiotoxicity; Cardiovascular Agents; Cells, Cultured; Induced Pluripotent Stem Cells; Ion Channels; Myocytes, Cardiac; Quinidine; Verapamil

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.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Cardiotoxicity; Cardiovascular Agents; Energy Metabolism; Enzyme Inhibitors; Heart Diseases; Male; Myocytes, Cardiac; Oxidative Stress; Pyruvates; Rats, Wistar; Signal Transduction; Trimetazidine; Ventricular Function, Left

After enhancing the survivorship of cancers, the impact of cardiovascular diseases on mortality is increasing among cancer patients. However, anticancer therapies pose a higher cardiovascular risk to patients. As prevention against cancer therapy-induced cardiomyopathy has yet to be explored, the preventive ability of concomitant cardiovascular medications against incident heart failure was assessed.. A retrospective, population-based study was run using anonymized integration of healthcare databases. All the Hungarian patients diagnosed with breast or colorectal carcinoma and undergoing chemotherapy or biological therapy were analysed. Participants were not treated with any anticancer therapy nor suffered from heart failure/dilated cardiomyopathy during the preceding observational period (≥6.5 years). The heart failure endpoint was established by I50 International Classification of Diseases codes upon discharge from hospital or issuance of an autopsy report.. Among the 9575 patients who were enrolled, the cumulative incidence of heart failure over 4 years was 6.9%. The time until the first heart failure event in the propensity score-matched treated and untreated groups was compared using Cox proportional-hazards models. A significant association between lower heart failure risk and concomitant statin therapy was observed (hazard ratio: 0.748, P = 0.038); the preventive ability was more pronounced in the anthracycline/capecitabine/platinum-treated subgroup (hazard ratio: 0.660, P = 0.032). For angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy, a significantly lower heart failure risk was also observed (hazard ratio: 0.809, P = 0.032). Among beta blockers, nebivolol administered to anthracycline/capecitabine-treated patients was associated with a nonsignificant trend to lower heart failure risk (hazard ratio: 0.584, P = 0.069).. Only concomitant statin and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapies were associated with significantly lower risk of anticancer therapy-related heart failure.

Topics: Antineoplastic Agents; Cardiomyopathies; Cardiotoxicity; Cardiovascular Agents; Databases, Factual; Female; Heart Failure; Humans; Hungary; Incidence; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Protective Factors; Retrospective Studies; Risk Adjustment

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h

Topics: Animals; Biomarkers, Pharmacological; Blood Pressure; Cardiotoxicity; Cardiovascular Agents; Heart Rate; Ivabradine; Male; Phenethylamines; Pyridazines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides

Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.. Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.. Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Calcium Signaling; Calcium-Binding Proteins; Cardiotoxicity; Cardiovascular Agents; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Doxorubicin; Female; Heart Diseases; Male; Mammary Neoplasms, Experimental; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Rats, Wistar; Simendan; Time Factors

Left ventricular (LV) dysfunction due to anthracycline-induced cardiotoxicity (AIC) has been believed to be irreversible. However, this has not been confirmed and standard medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers may lead to its recovery.. We thus retrospectively studied 350 cancer patients receiving anthracycline-based chemotherapy from 2001 to 2015 in our institution. Fifty-two patients (14.9%) developed AIC with a decrease in LV ejection fraction (LVEF) of 24.1% at a median time of 6 months [interquartile range (IQR) 4-22 months] after anthracycline therapy. By multivariate analysis, AIC was independently associated with cardiac comorbidities including ischemic heart disease, valvular heart disease, arrhythmia, and cardiomyopathy [odds ratio (OR) 6.00; 95% confidence interval (CI) 2.27-15.84, P = 0.00044), lower baseline LVEF (OR per 1% 1.09; 95% CI 1.04-1.14, P = 0.00034). During the median follow-up of 3.2 years, LV systolic dysfunction recovered among 33 patients (67.3%) with a median time of 4 months (IQR 2-6 months), which was independently associated with the introduction of standard medical treatment for HF (OR 9.39; 95% CI 2.27-52.9, P = 0.0014) by multivariate analysis.. Early initiation of standard medical treatment for HF may lead to LV functional recovery in AIC.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Cardiovascular Agents; Female; Heart Failure; Humans; Male; Middle Aged; Neoplasms; Recovery of Function; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

The use of vascular endothelial growth factor inhibitors such as sorafenib is limited by a risk of severe cardiovascular toxicity. A 28-year-old man with acute myeloid leukemia treated with prednisone, tacrolimus, and sorafenib following stem cell transplantation presented with severe bilateral lower extremity claudication. The patient was discharged against medical advice prior to finalizing a cardiovascular evaluation, but returned 1 week later with signs suggestive of septic shock. Laboratory tests revealed troponin I of 12.63 ng/mL, BNP of 1690 pg/mL, and negative infectious workup. Electrocardiogram showed sinus tachycardia and new pathologic Q waves in the anterior leads. Coronary angiography revealed severe multivessel coronary artery disease. Peripheral angiography revealed severely diseased left anterior and posterior tibial arteries, tibioperoneal trunk, and peroneal artery, and subtotal occlusion of the right posterior tibial artery. Multiple coronary and peripheral drug-eluting stents were implanted. An intra-aortic balloon pump was placed. Cardiac magnetic resonance imaging revealed chronic left ventricular infarction with some viability, 17% ejection fraction, and left ventricular mural thrombi. The patient opted for medical management. Persistent symptoms 9 months later led to repeat angiography, showing total occlusion of the second obtuse marginal artery due to in-stent restenosis with proximal stent fracture, and chronic total occlusion of the right internal iliac artery extending to the pudendal branch. Cardiac positron emission tomography/computed tomography viability study demonstrated viable myocardium, deeming revascularization appropriate. Symptom resolution was obtained with no recurrences. Sorafenib-associated vasculopathy may follow a fulminant course. Multimodality cardiovascular imaging is essential for optimal management.

Topics: Adult; Antineoplastic Agents; Cardiotoxicity; Cardiovascular Agents; Coronary Artery Disease; Coronary Restenosis; Defibrillators; Defibrillators, Implantable; Drug-Eluting Stents; Electric Countershock; Endovascular Procedures; Humans; Intra-Aortic Balloon Pumping; Leukemia, Myeloid, Acute; Male; Myocardial Infarction; Peripheral Arterial Disease; Protein Kinase Inhibitors; Sorafenib; Treatment Outcome

Induced pluripotent stem cell (iPSC)-based cardiac regenerative medicine requires the efficient generation, structural soundness and proper functioning of mature cardiomyocytes, derived from the patient's somatic cells. The most important functional property of cardiomyocytes is the ability to contract. Currently available methods routinely used to test and quantify cardiomyocyte function involve techniques that are labor-intensive, invasive, require sophisticated instruments or can adversely affect cell vitality. We recently developed optical flow imaging method analyses and quantified cardiomyocyte contractile kinetics from video microscopic recordings without compromising cell quality. Specifically, our automated particle image velocimetry (PIV) analysis of phase-contrast video images captured at a high frame rate yields statistical measures characterizing the beating frequency, amplitude, average waveform and beat-to-beat variations. Thus, it can be a powerful assessment tool to monitor cardiomyocyte quality and maturity. Here we demonstrate the ability of our analysis to characterize the chronotropic responses of human iPSC-derived cardiomyocytes to a panel of ion channel modulators and also to doxorubicin, a chemotherapy agent with known cardiotoxic side effects. We conclude that the PIV-derived beat patterns can identify the elongation or shortening of specific phases in the contractility cycle, and the obtained chronotropic responses are in accord with known clinical outcomes. Hence, this system can serve as a powerful tool to screen the new and currently available pharmacological compounds for cardiotoxic effects.

Topics: Cardiotoxicity; Cardiovascular Agents; Cell Shape; Cells, Cultured; Doxorubicin; Drug Evaluation, Preclinical; Flow Cytometry; Heart Rate; Humans; Induced Pluripotent Stem Cells; Models, Biological; Myocytes, Cardiac

Heart failure is a common adverse effect associated with doxorubicin treatment. The aim of this study is to investigate the effect of ivabradine treatment on doxorubicin-induced heart failure in conscious rats. Rats were treated with doxorubicin (2.5 mg/kg/d) or ivabradine (10 mg/kg/d) alone or along with doxorubicin injections. Changes in heart rate variability (HRV), baroreflex sensitivity, left ventricular (LV) function, serum cardiac troponin T, and cardiac histological features were taken as index parameters for the development of heart failure. Ivabradine significantly reduced the elevated heart rate; normalized the parameters of LV function, dP/dtmax and the relaxation time constant (Tau); reduced the elevated serum level of cardiac troponin T; and minimized the cardiac structural abnormalities in doxorubicin-treated rats. Moreover, ivabradine significantly increased the diminished time domain parameters of HRV, SDNN and rMSSD, and decreased the elevated low frequency power and the low frequency/high frequency while having no effect on the reduced high frequency power. Consistently, ivabradine significantly lowered the elevated baroreflex sensitivity measured by sodium nitroprusside. In conclusion, ivabradine ameliorated the LV dysfunction induced by doxorubicin. Moreover, ivabradine increased the overall HRV and restored the autonomic balance by reducing the sympathetic over activation. Therefore, ivabradine may have a possible therapeutic potential against doxorubicin-induced heart failure.

Topics: Animals; Arterial Pressure; Autonomic Nervous System; Autonomic Nervous System Diseases; Baroreflex; Cardiotoxicity; Cardiovascular Agents; Cardiovascular System; Disease Models, Animal; Doxorubicin; Heart Failure; Heart Rate; Ivabradine; Male; Rats, Wistar; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses, and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.

Topics: Cardiotoxicity; Cardiovascular Agents; Cell Differentiation; Female; Healthy Volunteers; Humans; In Vitro Techniques; Induced Pluripotent Stem Cells; Male; Myocytes, Cardiac; Phenotype; Reproducibility of Results

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Cardiotoxicity; Cardiovascular Agents; Cyperus; Cytoprotection; Disease Models, Animal; Ethanol; Isoproterenol; Male; Metoprolol; Myocardial Infarction; Myocardium; Necrosis; Phytotherapy; Plant Extracts; Plants, Medicinal; Ramipril; Rats, Wistar; Rhizome; Solvents

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analysis, integration and prediction. This paper describes a Workshop on Computational Cardiovascular Science that created an international, interdisciplinary and inter-sectorial forum to define the next steps for a human-based approach to disease supported by computational methodologies. The main ideas highlighted were (i) a shift towards human-based methodologies, spurred by advances in new in silico, in vivo, in vitro, and ex vivo techniques and the increasing acknowledgement of the limitations of animal models. (ii) Computational approaches complement, expand, bridge, and integrate in vitro, in vivo, and ex vivo experimental and clinical data and methods, and as such they are an integral part of human-based methodologies in pharmacology and medicine. (iii) The effective implementation of multi- and interdisciplinary approaches, teams, and training combining and integrating computational methods with experimental and clinical approaches across academia, industry, and healthcare settings is a priority. (iv) The human-based cross-disciplinary approach requires experts in specific methodologies and domains, who also have the capacity to communicate and collaborate across disciplines and cross-sector environments. (v) This new translational domain for human-based cardiology and pharmacology requires new partnerships supported financially and institutionally across sectors. Institutional, organizational, and social barriers must be identified, understood and overcome in each specific setting.

Topics: Animals; Biomarkers; Cardiac Imaging Techniques; Cardiology; Cardiotoxicity; Cardiovascular Agents; Cooperative Behavior; Diffusion of Innovation; Electrophysiologic Techniques, Cardiac; Heart Diseases; Humans; Interdisciplinary Communication; Models, Cardiovascular; Patient-Specific Modeling; Pharmacology; Predictive Value of Tests; Prognosis; Public-Private Sector Partnerships; Translational Research, Biomedical

Topics: Anesthesia, Local; Anesthetics, Local; Cardiotoxicity; Cardiovascular Agents; Heart; Humans