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Cardiovascular Toxicology
Journal Prestige (SJR): 0.836  Citation Impact (citeScore): 2 Number of Followers: 6  Hybrid journal (It can contain Open Access articles)ISSN (Print) 1559-0259 - ISSN (Online) 1530-7905 Published by Springer-Verlag  [2570 journals]
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- Various Manifestations of 5-Fluorouracil Cardiotoxicity: A Multicenter
Case Series and Review of Literature- Abstract: Abstract 5-Fluorouracil is a key element to the treatment of colon cancer. But it is also one of the most cardiotoxic chemotherapies, and the management of those that experience cardiotoxicity can be challenging. We present three cases of 5-FU cardiac toxicity that manifested as myocardial infarction, cardiogenic shock, and ventricular fibrillation. Additionally, we discuss the current literature regarding 5-fluorouracil cardiotoxicity mechanisms as well as management.
PubDate: 2020-01-10
- Abstract: Abstract 5-Fluorouracil is a key element to the treatment of colon cancer. But it is also one of the most cardiotoxic chemotherapies, and the management of those that experience cardiotoxicity can be challenging. We present three cases of 5-FU cardiac toxicity that manifested as myocardial infarction, cardiogenic shock, and ventricular fibrillation. Additionally, we discuss the current literature regarding 5-fluorouracil cardiotoxicity mechanisms as well as management.
- How the Deuteration of Dronedarone Can Modify Its Cardiovascular Profile:
In Vivo Characterization of Electropharmacological Effects of Poyendarone,
a Deuterated Analogue of Dronedarone- Abstract: Abstract Since deuterium replacement has a potential to modulate pharmacodynamics, pharmacokinetics and toxicity, we developed deuterated dronedarone; poyendarone, and assessed its cardiovascular effects. Poyendarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s was intravenously administered to the halothane-anesthetized dogs (n = 4), which provided peak plasma concentrations of 108 ± 10 and 1120 ± 285 ng/mL, respectively. The 0.3 mg/kg shortened the ventricular repolarization period. The 3 mg/kg transiently increased the heart rate at 5 min but decreased at 45 min, and elevated the total peripheral vascular resistance and left ventricular preload, whereas it reduced the mean blood pressure at 5 min, left ventricular contractility and cardiac output. The transient tachycardic action is considered to be induced by the hypotension-induced, reflex-mediated increase of sympathetic tone. The 3 mg/kg delayed both intra-atrial and intra-ventricular conductions, indicating Na+ channel inhibitory action. Moreover, the 3 mg/kg transiently shortened the ventricular repolarization period at 5 min. No significant change was detected in the late repolarization by poyendarone, indicating it might not hardly significantly alter rapidly activating delayed-rectifier K+ current (IKr). Poyendarone prolonged the atrial effective refractory period greater than the ventricular parameter. When compared with dronedarone, poyendarone showed similar pharmacokinetics of dronedarone, but reduced β-adrenoceptor blocking activity as well as the cardio-suppressive effect. Poyendarone failed to inhibit IKr and showed higher atrial selectivity in prolonging the effective refractory period of atrium versus ventricle. Thus, the deuteration may be an effective way to improve the cardiovascular profile of dronedarone. Poyendarone is a promising anti-atrial fibrillatory drug candidate.
PubDate: 2020-01-02
- Abstract: Abstract Since deuterium replacement has a potential to modulate pharmacodynamics, pharmacokinetics and toxicity, we developed deuterated dronedarone; poyendarone, and assessed its cardiovascular effects. Poyendarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s was intravenously administered to the halothane-anesthetized dogs (n = 4), which provided peak plasma concentrations of 108 ± 10 and 1120 ± 285 ng/mL, respectively. The 0.3 mg/kg shortened the ventricular repolarization period. The 3 mg/kg transiently increased the heart rate at 5 min but decreased at 45 min, and elevated the total peripheral vascular resistance and left ventricular preload, whereas it reduced the mean blood pressure at 5 min, left ventricular contractility and cardiac output. The transient tachycardic action is considered to be induced by the hypotension-induced, reflex-mediated increase of sympathetic tone. The 3 mg/kg delayed both intra-atrial and intra-ventricular conductions, indicating Na+ channel inhibitory action. Moreover, the 3 mg/kg transiently shortened the ventricular repolarization period at 5 min. No significant change was detected in the late repolarization by poyendarone, indicating it might not hardly significantly alter rapidly activating delayed-rectifier K+ current (IKr). Poyendarone prolonged the atrial effective refractory period greater than the ventricular parameter. When compared with dronedarone, poyendarone showed similar pharmacokinetics of dronedarone, but reduced β-adrenoceptor blocking activity as well as the cardio-suppressive effect. Poyendarone failed to inhibit IKr and showed higher atrial selectivity in prolonging the effective refractory period of atrium versus ventricle. Thus, the deuteration may be an effective way to improve the cardiovascular profile of dronedarone. Poyendarone is a promising anti-atrial fibrillatory drug candidate.
- Rho Kinase Inhibition by Fasudil Attenuates Adriamycin-Induced Chronic
Heart Injury- Abstract: Abstract Adriamycin (ADR)-induced chronic heart injury (CHI) is a serious complication of chemotherapy. The present study was designed to assess the ability of fasudil, a Rho kinase inhibitor, to prevent ADR-induced CHI. Forty male 6-week-old C57BL6 mice were randomly divided into the following four groups: (1) control group, (2) CHI induced by adriamycin (ADR group), (3) CHI plus low dose fasudil (ADR + L group), and (4) CHI plus high dose fasudil (ADR + H group). Animals from groups 2–4 received ADR (2.5 mg/kg, i.p.) once a week for 8 weeks, and the control group received saline. Meanwhile, the animals in groups 3–4 received 2 mg/kg/day or 10 mg/kg/day fasudil, respectively. After measurement of cardiac functions, blood samples were collected for biochemical assays. The hearts were excised for histological, immunohistochemistry and western blot study, respectively. Adriamycin produced evident cardiac damage revealed by cardiac functions changes: decreased left ventricular fractional shortening (FS), left ventricular ejection fraction (EF), increased left ventricular volume, cardiac injury marker changes (increased creatine kinase, lactate dehydrogenase), antioxidant enzymes activity changes (decreased superoxide dismutase), and lipid peroxidation (elevated malondialdehyde) to the control group. Fasudil treatment notably ameliorated ADR-induced cardiac damage, restored heart function, suppressed cell apoptosis and senescence, ameliorated redox imbalance, and DNA damage. Fasudil has a protective effect on ADR-induced chronic heart injury, which partially attributed to its antioxidant, anti-apoptotic effects of inhibiting the RhoA/Rho kinase (ROCK) signaling pathway.
PubDate: 2020-01-01
- Abstract: Abstract Adriamycin (ADR)-induced chronic heart injury (CHI) is a serious complication of chemotherapy. The present study was designed to assess the ability of fasudil, a Rho kinase inhibitor, to prevent ADR-induced CHI. Forty male 6-week-old C57BL6 mice were randomly divided into the following four groups: (1) control group, (2) CHI induced by adriamycin (ADR group), (3) CHI plus low dose fasudil (ADR + L group), and (4) CHI plus high dose fasudil (ADR + H group). Animals from groups 2–4 received ADR (2.5 mg/kg, i.p.) once a week for 8 weeks, and the control group received saline. Meanwhile, the animals in groups 3–4 received 2 mg/kg/day or 10 mg/kg/day fasudil, respectively. After measurement of cardiac functions, blood samples were collected for biochemical assays. The hearts were excised for histological, immunohistochemistry and western blot study, respectively. Adriamycin produced evident cardiac damage revealed by cardiac functions changes: decreased left ventricular fractional shortening (FS), left ventricular ejection fraction (EF), increased left ventricular volume, cardiac injury marker changes (increased creatine kinase, lactate dehydrogenase), antioxidant enzymes activity changes (decreased superoxide dismutase), and lipid peroxidation (elevated malondialdehyde) to the control group. Fasudil treatment notably ameliorated ADR-induced cardiac damage, restored heart function, suppressed cell apoptosis and senescence, ameliorated redox imbalance, and DNA damage. Fasudil has a protective effect on ADR-induced chronic heart injury, which partially attributed to its antioxidant, anti-apoptotic effects of inhibiting the RhoA/Rho kinase (ROCK) signaling pathway.
- Myocardial Repolarization Parameters and Neutrophil-to-Lymphocyte Ratio
are Associated with Cardiotoxicity in Carbon Monoxide Poisoning- Abstract: Abstract The present study aims to examine the clinical values of complete blood count (CBC) bioindicators and corrected QT (QTc), Tpeak − Tend interval (Tp−e), Tpeak dispersion (Tp disp), and Tp−e/QT ratio that are the parameters of myocardial repolarization (M-rep) for cardiotoxicity, which develops due to acute carbon monoxide (CO) intoxication in patients admitted to the emergency service. This retrospective, cross-sectional, observational, and single-center study was conducted between April and June 2019. Statistical analysis was performed using the SPSS 23.0 software. Data of 234 participants were analyzed. Of these, 54.9% (n = 129) were female. Neutrophil-to-lymphocyte ratio (NLR), QTc, Tp–e values were significantly high in the CO intoxication group (p < 0.001, p < 0.001, and p < 0.001, respectively), whereas Tp−e/QTc ratio was significantly lower in the CO intoxication group than that in the control group (p < 0.001). NLR, Tp−e, Tp disp values were significantly high in the myocardial injury (M-inj) group (p < 0.001, p = 0.003, and p = 0.018, respectively). Furthermore, Tp−e/QTc ratio was significantly low in the M-inj group (p = 0.002). M-rep parameters and NLR are associated with CO intoxication and the development of M-inj. Moreover, these bioindicators and can provide clinicians an early indication of M-inj.
PubDate: 2019-12-20
- Abstract: Abstract The present study aims to examine the clinical values of complete blood count (CBC) bioindicators and corrected QT (QTc), Tpeak − Tend interval (Tp−e), Tpeak dispersion (Tp disp), and Tp−e/QT ratio that are the parameters of myocardial repolarization (M-rep) for cardiotoxicity, which develops due to acute carbon monoxide (CO) intoxication in patients admitted to the emergency service. This retrospective, cross-sectional, observational, and single-center study was conducted between April and June 2019. Statistical analysis was performed using the SPSS 23.0 software. Data of 234 participants were analyzed. Of these, 54.9% (n = 129) were female. Neutrophil-to-lymphocyte ratio (NLR), QTc, Tp–e values were significantly high in the CO intoxication group (p < 0.001, p < 0.001, and p < 0.001, respectively), whereas Tp−e/QTc ratio was significantly lower in the CO intoxication group than that in the control group (p < 0.001). NLR, Tp−e, Tp disp values were significantly high in the myocardial injury (M-inj) group (p < 0.001, p = 0.003, and p = 0.018, respectively). Furthermore, Tp−e/QTc ratio was significantly low in the M-inj group (p = 0.002). M-rep parameters and NLR are associated with CO intoxication and the development of M-inj. Moreover, these bioindicators and can provide clinicians an early indication of M-inj.
- Cardioprotective Effects and Duration of Beta Blocker Therapy in
Anthracycline-Treated Patients: A Systematic Review and Meta-analysis- Abstract: Abstract Anthracycline-containing chemotherapy is commonly associated with irreversible cardiovascular toxicity. Beta blockers are currently recommended as first-line drugs for improving cardiac function. However, the effects of beta blocker on cardiac preservation and the duration of beta blocker intervention therapy in anthracycline-treated patients remain unclear. We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (published between January, 2000 and January, 2019) to determine the effectiveness of cardiac preservation of beta blocker in anthracycline-treated patients by accessing the change in left ventricular ejection fraction (LVEF) from pre- to post-chemotherapy. In addition, we conducted subgroup analysis based on the duration of beta blocker cardioprotective intervention and accumulative anthracycline dose. 11 RCTs were finally included. Beta blockers were associated with a significant smaller drop in the LVEF change (MD = 2.87, 95% CI 0.64 to 5.11, p = 0.01) compared to control groups. Besides, a subgroup analysis according to duration of beta blocker-based cardioprotective intervention (< 6 months vs = 6 months) showed significant subgroup difference in the LVEF change (MD = − 0.05, 95% CI − 0.91 to 0.81, p = 0.91; MD = 6.48, 95% CI 2.44 to 10.52, p = 0.002). An additional subgroup analysis according to accumulative anthracycline dose showed statistically significant difference in the LVEF change (MD = 4.61, 95% CI 0.78 to 8.45, p = 0.02) with moderate accumulative dose of anthracycline (doxorubicin between 250 and 400 mg/m2). Prophylactic administration of beta blocker-based cardioprotective therapy may be beneficial to the myocardial preservation in anthracycline-treated patients. And long-term use of beta blocker appears to have a positive effect on ameliorating anthracycline-induced cardiomyopathy, especially in patients exposed to moderate accumulative doses of anthracycline.
PubDate: 2019-12-12
- Abstract: Abstract Anthracycline-containing chemotherapy is commonly associated with irreversible cardiovascular toxicity. Beta blockers are currently recommended as first-line drugs for improving cardiac function. However, the effects of beta blocker on cardiac preservation and the duration of beta blocker intervention therapy in anthracycline-treated patients remain unclear. We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (published between January, 2000 and January, 2019) to determine the effectiveness of cardiac preservation of beta blocker in anthracycline-treated patients by accessing the change in left ventricular ejection fraction (LVEF) from pre- to post-chemotherapy. In addition, we conducted subgroup analysis based on the duration of beta blocker cardioprotective intervention and accumulative anthracycline dose. 11 RCTs were finally included. Beta blockers were associated with a significant smaller drop in the LVEF change (MD = 2.87, 95% CI 0.64 to 5.11, p = 0.01) compared to control groups. Besides, a subgroup analysis according to duration of beta blocker-based cardioprotective intervention (< 6 months vs = 6 months) showed significant subgroup difference in the LVEF change (MD = − 0.05, 95% CI − 0.91 to 0.81, p = 0.91; MD = 6.48, 95% CI 2.44 to 10.52, p = 0.002). An additional subgroup analysis according to accumulative anthracycline dose showed statistically significant difference in the LVEF change (MD = 4.61, 95% CI 0.78 to 8.45, p = 0.02) with moderate accumulative dose of anthracycline (doxorubicin between 250 and 400 mg/m2). Prophylactic administration of beta blocker-based cardioprotective therapy may be beneficial to the myocardial preservation in anthracycline-treated patients. And long-term use of beta blocker appears to have a positive effect on ameliorating anthracycline-induced cardiomyopathy, especially in patients exposed to moderate accumulative doses of anthracycline.
- The Effects of Neuropeptide Y Overexpression on the Mouse Model of
Doxorubicin-Induced Cardiotoxicity- Abstract: Abstract Doxorubicin is a potent anticancer drug with cardiotoxicity hampering its use. Neuropeptide Y (NPY) is the most abundant neuropeptide in the heart and a co-transmitter of the sympathetic nervous system that plays a role in cardiac diseases. The aim of this work was to study the impact of NPY on doxorubicin-induced cardiotoxicity. Transgenic mice overexpressing NPY in noradrenergic neurons (NPY-OEDβH) and wild-type mice were treated with a single dose of doxorubicin. Doxorubicin caused cardiotoxicity in both genotypes as demonstrated by decreased weight gain, tendency to reduced ejection fraction, and changes in the expression of several genes relevant to cardiac pathology. Doxorubicin resulted in a tendency to lower ejection fraction in NPY-OEDβH mice more than in wild-type mice. In addition, gain in the whole body lean mass gain was decreased only in NPY-OEDβH mice, suggesting a more severe impact of doxorubicin in this genotype. The effects of doxorubicin on genes expressed in the heart were similar between NPY-OEDβH and wild-type mice. The results demonstrate that doxorubicin at a relatively low dose caused significant cardiotoxicity. There were differences between NPY-OEDβH and wild-type mice in their responses to doxorubicin that suggest NPY to increase susceptibility to cardiotoxicity. This may point to the therapeutic implications as suggested for NPY system in other cardiovascular diseases.
PubDate: 2019-12-06
- Abstract: Abstract Doxorubicin is a potent anticancer drug with cardiotoxicity hampering its use. Neuropeptide Y (NPY) is the most abundant neuropeptide in the heart and a co-transmitter of the sympathetic nervous system that plays a role in cardiac diseases. The aim of this work was to study the impact of NPY on doxorubicin-induced cardiotoxicity. Transgenic mice overexpressing NPY in noradrenergic neurons (NPY-OEDβH) and wild-type mice were treated with a single dose of doxorubicin. Doxorubicin caused cardiotoxicity in both genotypes as demonstrated by decreased weight gain, tendency to reduced ejection fraction, and changes in the expression of several genes relevant to cardiac pathology. Doxorubicin resulted in a tendency to lower ejection fraction in NPY-OEDβH mice more than in wild-type mice. In addition, gain in the whole body lean mass gain was decreased only in NPY-OEDβH mice, suggesting a more severe impact of doxorubicin in this genotype. The effects of doxorubicin on genes expressed in the heart were similar between NPY-OEDβH and wild-type mice. The results demonstrate that doxorubicin at a relatively low dose caused significant cardiotoxicity. There were differences between NPY-OEDβH and wild-type mice in their responses to doxorubicin that suggest NPY to increase susceptibility to cardiotoxicity. This may point to the therapeutic implications as suggested for NPY system in other cardiovascular diseases.
- MDMA Induced Cardio-toxicity and Pathological Myocardial Effects: A
Systematic Review of Experimental Data and Autopsy Findings- Abstract: Abstract 3,4-Methylenedioxymethamphetamine (MDMA), more commonly known as “ecstasy,” is a semi-synthetic entactogenic phenylethylamine. In recent years it has gained popularity as a recreational drug whose use has registered an upward trend especially among adolescents and young adults. Despite its unwarranted reputation of being a “safe” drug, the actual scientific data denote that it actually leaves a trail of cardio-toxicity, above and beyond its neurotoxicity and other somatic effects. Both experimental and clinical data, in fact, indicate that ecstasy can alter cardiac function leading to rhythm disturbances, myocardial infarction, and even sudden cardiac death. We reviewed and summarized the bio-medical literature on the cardiovascular response to MDMA both in humans and laboratory animals. The aim was to elucidate the various pathophysiological mechanisms involved, as well as the clinical, autoptic, and experimental findings underlying MDMA-induced cardio-toxicity. Finally, an illustrative case report of ecstasy-induced adolescent death due to acute cardio-toxicity was described so as to highlight some key features.
PubDate: 2019-12-01
- Abstract: Abstract 3,4-Methylenedioxymethamphetamine (MDMA), more commonly known as “ecstasy,” is a semi-synthetic entactogenic phenylethylamine. In recent years it has gained popularity as a recreational drug whose use has registered an upward trend especially among adolescents and young adults. Despite its unwarranted reputation of being a “safe” drug, the actual scientific data denote that it actually leaves a trail of cardio-toxicity, above and beyond its neurotoxicity and other somatic effects. Both experimental and clinical data, in fact, indicate that ecstasy can alter cardiac function leading to rhythm disturbances, myocardial infarction, and even sudden cardiac death. We reviewed and summarized the bio-medical literature on the cardiovascular response to MDMA both in humans and laboratory animals. The aim was to elucidate the various pathophysiological mechanisms involved, as well as the clinical, autoptic, and experimental findings underlying MDMA-induced cardio-toxicity. Finally, an illustrative case report of ecstasy-induced adolescent death due to acute cardio-toxicity was described so as to highlight some key features.
- Therapeutic Effects of Liraglutide, Oxytocin and Granulocyte
Colony-Stimulating Factor in Doxorubicin-Induced Cardiomyopathy Model: An
Experimental Animal Study- Abstract: Abstract Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague–Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in this rat model.
PubDate: 2019-12-01
- Abstract: Abstract Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague–Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in this rat model.
- 2,3,7,8-Tetrachlorodibenzo- p -dioxin Induces Vascular Dysfunction That is
Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression- Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. Graphical TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.
PubDate: 2019-12-01
- Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. Graphical TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.
- Acylated Ghrelin Protects the Hearts of Rats from Doxorubicin-Induced
Fas/FasL Apoptosis by Stimulating SERCA2a Mediated by Activation of PKA
and Akt- Abstract: Abstract This study investigated if the cardioprotective effect of acylated ghrelin (AG) against doxorubicin (DOX)-induced cardiac toxicity in rats involves inhibition of Fas/FasL-mediated cell death. It also investigated if such an effect is mediated by restoring Ca+2 homeostasis from the aspect of stimulation of SERCA2a receptors. Adult male Wistar rats were divided into 4 groups (20 rats/each) as control, control + AG, DOX, and DOX + AG. AG was co-administered to all rats consecutively for 35 days. In addition, isolated cardiomyocytes were cultured and treated with AG in the presence or absence of DOX with or without pre-incubation with [d-Lys3]-GHRP-6 (a AG receptor antagonist), VIII (]an Akt inhibitor), or KT-5720 (a PKA inhibitor). AG increased LVSP, dp/dtmax, and dp/dtmin in both control and DOX-treated animals and improved cardiac ultrastructural changes in DOX-treated rats. It also inhibited ROS in control rats and lowered LVEDP, intracellular levels of ROS and Ca2+, and activity of calcineurin in LVs of DOX-treated rats. Concomitantly, it inhibited LV NFAT-4 nuclear translocation and downregulated their protein levels of Fas and FasL. Mechanistically, in control or DOX-treated hearts or cells, AG upregulated the levels of SERCA2a and increased the activities of PKA and Akt, leading to increase phosphorylation of phospholamban at Ser16 and Thr17. All these effects were abolished by d-Lys3-GHRP-6, VIII, or KT-5720 and were independent of food intake or GH/IGF-1. In conclusion, AG cardioprotection against DOX involves inhibition of extrinsic cell death and restoring normal Ca+2 homeostasis.
PubDate: 2019-12-01
- Abstract: Abstract This study investigated if the cardioprotective effect of acylated ghrelin (AG) against doxorubicin (DOX)-induced cardiac toxicity in rats involves inhibition of Fas/FasL-mediated cell death. It also investigated if such an effect is mediated by restoring Ca+2 homeostasis from the aspect of stimulation of SERCA2a receptors. Adult male Wistar rats were divided into 4 groups (20 rats/each) as control, control + AG, DOX, and DOX + AG. AG was co-administered to all rats consecutively for 35 days. In addition, isolated cardiomyocytes were cultured and treated with AG in the presence or absence of DOX with or without pre-incubation with [d-Lys3]-GHRP-6 (a AG receptor antagonist), VIII (]an Akt inhibitor), or KT-5720 (a PKA inhibitor). AG increased LVSP, dp/dtmax, and dp/dtmin in both control and DOX-treated animals and improved cardiac ultrastructural changes in DOX-treated rats. It also inhibited ROS in control rats and lowered LVEDP, intracellular levels of ROS and Ca2+, and activity of calcineurin in LVs of DOX-treated rats. Concomitantly, it inhibited LV NFAT-4 nuclear translocation and downregulated their protein levels of Fas and FasL. Mechanistically, in control or DOX-treated hearts or cells, AG upregulated the levels of SERCA2a and increased the activities of PKA and Akt, leading to increase phosphorylation of phospholamban at Ser16 and Thr17. All these effects were abolished by d-Lys3-GHRP-6, VIII, or KT-5720 and were independent of food intake or GH/IGF-1. In conclusion, AG cardioprotection against DOX involves inhibition of extrinsic cell death and restoring normal Ca+2 homeostasis.
- Coenzyme Q10 Alleviates Chronic Nucleoside Reverse Transcriptase
Inhibitor-Induced Premature Endothelial Senescence- Abstract: Abstract Human immunodeficiency virus (HIV)-infected patients undergoing antiretroviral therapy are afforded an increased lifespan but also exhibit an elevated incidence of cardiovascular disease. HIV therapy uses a combination drug approach, and nucleoside reverse transcriptase inhibitors (NRTI) are a backbone of this therapy. Endothelial dysfunction is an initiating event in cardiovascular disease etiology, and in our prior studies, NRTIs induced an endothelial dysfunction that was dependent upon mitochondrial oxidative stress. Moreover, short-term NRTI administration induced a mitophagy-associated endothelial toxicity and increased reactive oxygen species (ROS) production that was rescued by coenzyme Q10 (Q10) or overexpression of a mitochondrial antioxidant enzyme. Thus, our objective was to examine mitochondrial toxicity in endothelial cells after chronic NRTI treatment and evaluate Q10 as a potential adjunct therapy for preventing NRTI-induced mitochondrial toxicity. Human aortic endothelial cells (HAEC) were exposed to chronic NRTI treatment, with or without Q10. ROS production, cell proliferation rate, levels of senescence, and mitochondrial bioenergetic function were determined. Chronic NRTI increased ROS production but decreased population doubling. In addition, NRTI increased the accumulation of β-galactosidase, indicative of an accelerated rate of senescence. Moreover, ATP-linked respiration was diminished. Co-treatment with Q10 delayed the onset of NRTI-induced senescence, decreased ROS production and rescued the cells’ mitochondrial respiration rate. Thus, our findings may suggest antioxidant enrichment approaches for reducing the cardiovascular side effects of NRTI therapy.
PubDate: 2019-12-01
- Abstract: Abstract Human immunodeficiency virus (HIV)-infected patients undergoing antiretroviral therapy are afforded an increased lifespan but also exhibit an elevated incidence of cardiovascular disease. HIV therapy uses a combination drug approach, and nucleoside reverse transcriptase inhibitors (NRTI) are a backbone of this therapy. Endothelial dysfunction is an initiating event in cardiovascular disease etiology, and in our prior studies, NRTIs induced an endothelial dysfunction that was dependent upon mitochondrial oxidative stress. Moreover, short-term NRTI administration induced a mitophagy-associated endothelial toxicity and increased reactive oxygen species (ROS) production that was rescued by coenzyme Q10 (Q10) or overexpression of a mitochondrial antioxidant enzyme. Thus, our objective was to examine mitochondrial toxicity in endothelial cells after chronic NRTI treatment and evaluate Q10 as a potential adjunct therapy for preventing NRTI-induced mitochondrial toxicity. Human aortic endothelial cells (HAEC) were exposed to chronic NRTI treatment, with or without Q10. ROS production, cell proliferation rate, levels of senescence, and mitochondrial bioenergetic function were determined. Chronic NRTI increased ROS production but decreased population doubling. In addition, NRTI increased the accumulation of β-galactosidase, indicative of an accelerated rate of senescence. Moreover, ATP-linked respiration was diminished. Co-treatment with Q10 delayed the onset of NRTI-induced senescence, decreased ROS production and rescued the cells’ mitochondrial respiration rate. Thus, our findings may suggest antioxidant enrichment approaches for reducing the cardiovascular side effects of NRTI therapy.
- The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for
Erythromycin Arrhythmogenicity Testing- Abstract: Abstract Erythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (IKr) without affecting either the slow delayed rectifying potassium current (IKs) or inward rectifying potassium current (IK1). Erythromycin exerts this effect in the range of 1.5–100 μM. However, the mechanism of action underlying its cardiotoxic effect and its role in the induction of arrhythmias, especially in multicellular cardiac experimental models, remain unclear. In this study, the re-entry formation, conduction velocity, and maximum capture rate were investigated in a monolayer of human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a healthy donor and in a neonatal rat ventricular myocyte (NRVM) monolayer using the optical mapping method under erythromycin concentrations of 15, 30, and 45 μM. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12 ± 9% at concentrations of 15–45 μM as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28 ± 12% (p < 0.01). In contrast, the tests on the NRVM monolayer showed no significant effect on the MCR. The results of the arrhythmogenicity test provided evidence for a “window” of concentrations of the drug (15–30 μM) at which the probability of re-entry increased.
PubDate: 2019-12-01
- Abstract: Abstract Erythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (IKr) without affecting either the slow delayed rectifying potassium current (IKs) or inward rectifying potassium current (IK1). Erythromycin exerts this effect in the range of 1.5–100 μM. However, the mechanism of action underlying its cardiotoxic effect and its role in the induction of arrhythmias, especially in multicellular cardiac experimental models, remain unclear. In this study, the re-entry formation, conduction velocity, and maximum capture rate were investigated in a monolayer of human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a healthy donor and in a neonatal rat ventricular myocyte (NRVM) monolayer using the optical mapping method under erythromycin concentrations of 15, 30, and 45 μM. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12 ± 9% at concentrations of 15–45 μM as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28 ± 12% (p < 0.01). In contrast, the tests on the NRVM monolayer showed no significant effect on the MCR. The results of the arrhythmogenicity test provided evidence for a “window” of concentrations of the drug (15–30 μM) at which the probability of re-entry increased.
- Role of Speckle Tracking Echocardiography in the Evaluation of Breast
Cancer Patients Undergoing Chemotherapy: Review and Meta-analysis of the
Literature- Abstract: Abstract Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.
PubDate: 2019-12-01
- Abstract: Abstract Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.
- Intermittent Exposure to Chlorpyrifos Differentially Impacts Neuroreflex
Control of Cardiorespiratory Function in Rats- Abstract: Abstract Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds.
PubDate: 2019-12-01
- Abstract: Abstract Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds.
- Direct and Indirect Effect of Air Particles Exposure Induce Nrf2-Dependent
Cardiomyocyte Cellular Response In Vitro- Abstract: Abstract Air particulate matter has been associated with adverse effects in the cardiorespiratory system leading to cytotoxic and pro-inflammatory effects. Particulate matter-associated cardiac effects may be direct or indirect. While direct interactions may occur when inhaled ultrafine particles and/or particle components cross the air–blood barrier reaching the cardiac tissue, indirect interactions may occur as the result of pulmonary inflammation and consequently the release of inflammatory and oxidative mediators into the blood circulation. The aim of the study is to investigate the direct or indirectly the effect of Urban Air particles from downtown Buenos Aires (UAP-BA) and residual oil fly ash (ROFA), a surrogate of ambient air pollution, on cardiomyocytes (HL-1 cells). HL-1 cultured cells were directly exposed to particulate matter [UAP-BA (10–200 µg/ml), ROFA (1–100 µg/ml)] or indirectly exposed to conditioned media (CM) from particle-exposed alveolar macrophages (AM). Metabolic activity, reactive oxygen species (ROS), and Nrf2 expression were assessed by MTT, DHR 123, and immunocytochemistry techniques, respectively. We found that direct exposure of cardiomyocytes to UAP-BA or ROFA increased ROS generation but the oxidative damage did not alter metabolic activity likely by a concomitant increase in the cytoplasmic and nuclear Nrf2 expression. However, indirect exposure through CM caused a marked reduction on cardiac metabolic activity probably due to the rise in ROS generation without Nrf2 translocation into the cell nuclei. In this in vitro model, our results indicate both direct and indirect PM effects on cardiomyocytes cells in culture. Our findings employing lung and cardiomyocytes cells provide support to the hypothesis that particle-induced cardiac alteration may possibly involve lung-derived mediators.
PubDate: 2019-12-01
- Abstract: Abstract Air particulate matter has been associated with adverse effects in the cardiorespiratory system leading to cytotoxic and pro-inflammatory effects. Particulate matter-associated cardiac effects may be direct or indirect. While direct interactions may occur when inhaled ultrafine particles and/or particle components cross the air–blood barrier reaching the cardiac tissue, indirect interactions may occur as the result of pulmonary inflammation and consequently the release of inflammatory and oxidative mediators into the blood circulation. The aim of the study is to investigate the direct or indirectly the effect of Urban Air particles from downtown Buenos Aires (UAP-BA) and residual oil fly ash (ROFA), a surrogate of ambient air pollution, on cardiomyocytes (HL-1 cells). HL-1 cultured cells were directly exposed to particulate matter [UAP-BA (10–200 µg/ml), ROFA (1–100 µg/ml)] or indirectly exposed to conditioned media (CM) from particle-exposed alveolar macrophages (AM). Metabolic activity, reactive oxygen species (ROS), and Nrf2 expression were assessed by MTT, DHR 123, and immunocytochemistry techniques, respectively. We found that direct exposure of cardiomyocytes to UAP-BA or ROFA increased ROS generation but the oxidative damage did not alter metabolic activity likely by a concomitant increase in the cytoplasmic and nuclear Nrf2 expression. However, indirect exposure through CM caused a marked reduction on cardiac metabolic activity probably due to the rise in ROS generation without Nrf2 translocation into the cell nuclei. In this in vitro model, our results indicate both direct and indirect PM effects on cardiomyocytes cells in culture. Our findings employing lung and cardiomyocytes cells provide support to the hypothesis that particle-induced cardiac alteration may possibly involve lung-derived mediators.
- Platelet Function in Cardiovascular Disease: Activation of Molecules and
Activation by Molecules- Abstract: Abstract Globally, one of the major causes of death is the cardiovascular disease (CVD), and platelets play an important role in thrombosis and atherosclerosis that led to death. Platelet activation can be done by different molecules, genes, pathways, and chemokines. Lipids activate platelets by inflammatory factors, and platelets are activated by receptors of peptide hormones, signaling and secreted proteins, microRNAs (miRNAs), and oxidative stress which also affect the platelet activation in older age. In addition, surface molecules on platelets can interact with other cells and chemokines in activated platelets and cause inflammation thrombosis events and CVD. However, these molecules activating platelets or being activated by platelets can be suggested as the markers to predict the clinical outcome of CVD and can be targeted to reduce thrombosis and atherosclerosis. However, hindering these molecules by other factors such as genes and receptors can reduce platelet activation and aggregation and targeting these molecules can control platelet interactions, thrombosis, and CVD. In addition, dual therapy with the receptor blockers and novel drugs results in better management of CVD patients. Overall, our review will emphasize on the molecules involved in the activation of platelets and on the molecules that are activated by platelets in CVD and discuss the molecules that can be blocked or targeted to reduce the thrombosis events and control CVD.
PubDate: 2019-11-29
- Abstract: Abstract Globally, one of the major causes of death is the cardiovascular disease (CVD), and platelets play an important role in thrombosis and atherosclerosis that led to death. Platelet activation can be done by different molecules, genes, pathways, and chemokines. Lipids activate platelets by inflammatory factors, and platelets are activated by receptors of peptide hormones, signaling and secreted proteins, microRNAs (miRNAs), and oxidative stress which also affect the platelet activation in older age. In addition, surface molecules on platelets can interact with other cells and chemokines in activated platelets and cause inflammation thrombosis events and CVD. However, these molecules activating platelets or being activated by platelets can be suggested as the markers to predict the clinical outcome of CVD and can be targeted to reduce thrombosis and atherosclerosis. However, hindering these molecules by other factors such as genes and receptors can reduce platelet activation and aggregation and targeting these molecules can control platelet interactions, thrombosis, and CVD. In addition, dual therapy with the receptor blockers and novel drugs results in better management of CVD patients. Overall, our review will emphasize on the molecules involved in the activation of platelets and on the molecules that are activated by platelets in CVD and discuss the molecules that can be blocked or targeted to reduce the thrombosis events and control CVD.
- Impact of Arterial Hypertension on Doxorubicin-Based Chemotherapy-Induced
Subclinical Cardiac Damage in Breast Cancer Patients- Abstract: Abstract Advances in oncologic therapies have allowed to achieve better outcomes and longer survival in many patients with breast cancer. Anthracyclines are cytotoxic antibiotics widely used in daily oncology practice. However, anthracyclines cause cardiotoxicity which is a limiting factor of its use. Cumulative dose of anthracyclines is the major cause of induced cardiotoxicity. According to previous clinical trials, the major predisposing high-risk factors for anthracycline-based chemotherapy-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as diabetes and hypertension. Experimental studies in animals confirm that hypertension may be a significant factor predisposing anthracycline-based chemotherapy cardiotoxicity. The main objective of our study was to identify the effect of pre-existing arterial hypertension on the development of subclinical cardiac damage during or after doxorubicin-based chemotherapy in breast cancer patients. The study was performed prospectively between March 2016 and January 2017 in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics Department of Oncology and Department of Cardiology. Data of 73 women with breast cancer treated with doxorubicin-based chemotherapy in outpatient clinic were analyzed. Statistically significant association between pre-existing arterial hypertension and left ventricular systolic dysfunction after completion of chemotherapy was observed (P < 0.004). Our study demonstrated that pre-existing arterial hypertension has a very important role in the development of anthracycline-based chemotherapy-induced cardiotoxicity, despite arterial hypertension control quality. Consequently, further studies evaluating impact of other risk factors and how early and sufficient management of arterial hypertension could influence the development of cardiotoxicity are needed to avoid permanent cardiac damage.
PubDate: 2019-11-29
- Abstract: Abstract Advances in oncologic therapies have allowed to achieve better outcomes and longer survival in many patients with breast cancer. Anthracyclines are cytotoxic antibiotics widely used in daily oncology practice. However, anthracyclines cause cardiotoxicity which is a limiting factor of its use. Cumulative dose of anthracyclines is the major cause of induced cardiotoxicity. According to previous clinical trials, the major predisposing high-risk factors for anthracycline-based chemotherapy-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as diabetes and hypertension. Experimental studies in animals confirm that hypertension may be a significant factor predisposing anthracycline-based chemotherapy cardiotoxicity. The main objective of our study was to identify the effect of pre-existing arterial hypertension on the development of subclinical cardiac damage during or after doxorubicin-based chemotherapy in breast cancer patients. The study was performed prospectively between March 2016 and January 2017 in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics Department of Oncology and Department of Cardiology. Data of 73 women with breast cancer treated with doxorubicin-based chemotherapy in outpatient clinic were analyzed. Statistically significant association between pre-existing arterial hypertension and left ventricular systolic dysfunction after completion of chemotherapy was observed (P < 0.004). Our study demonstrated that pre-existing arterial hypertension has a very important role in the development of anthracycline-based chemotherapy-induced cardiotoxicity, despite arterial hypertension control quality. Consequently, further studies evaluating impact of other risk factors and how early and sufficient management of arterial hypertension could influence the development of cardiotoxicity are needed to avoid permanent cardiac damage.
- The Role of Topoisomerase IIβ in the Mechanisms of Action of the
Doxorubicin Cardioprotective Agent Dexrazoxane- Abstract: Abstract Dexrazoxane is clinically used to reduce doxorubicin cardiotoxicity and anthracycline-induced extravasation injury. Dexrazoxane is a strong catalytic inhibitor of topoisomerase II. It can also undergo metabolism to form an iron-binding analog of EDTA. Dexrazoxane was originally thought to act by reducing iron-dependent doxorubicin-based oxidative stress. However, a competing hypothesis posits that dexrazoxane may be protective through its ability to inhibit and reduce topoisomerase IIβ protein levels in the heart. A primary neonatal rat myocyte model was used to study the mechanism by which dexrazoxane protects against doxorubicin-induced myocyte damage. This study characterized the kinetics of the rapid and nearly complete dexrazoxane-induced loss of topoisomerase IIβ protein from neonatal rat cardiac myocytes. Immunofluorescent staining of attached myocytes for topoisomerase IIβ revealed that most of the topoisomerase IIβ was localized to the nucleus, although it was also present in the cytoplasm. Dexrazoxane treatment resulted in an almost complete reduction of topoisomerase IIβ in the nucleus and a lesser reduction in the cytoplasm. The recovery of topoisomerase IIβ levels after a pulse topoisomerase IIβ inhibitory concentration of dexrazoxane occurred slowly, with partial recovery only occurring after 24 h. The ability of dexrazoxane to reduce doxorubicin-induced damage to myocytes was greatest when topoisomerase IIβ levels were at their lowest.
PubDate: 2019-11-26
- Abstract: Abstract Dexrazoxane is clinically used to reduce doxorubicin cardiotoxicity and anthracycline-induced extravasation injury. Dexrazoxane is a strong catalytic inhibitor of topoisomerase II. It can also undergo metabolism to form an iron-binding analog of EDTA. Dexrazoxane was originally thought to act by reducing iron-dependent doxorubicin-based oxidative stress. However, a competing hypothesis posits that dexrazoxane may be protective through its ability to inhibit and reduce topoisomerase IIβ protein levels in the heart. A primary neonatal rat myocyte model was used to study the mechanism by which dexrazoxane protects against doxorubicin-induced myocyte damage. This study characterized the kinetics of the rapid and nearly complete dexrazoxane-induced loss of topoisomerase IIβ protein from neonatal rat cardiac myocytes. Immunofluorescent staining of attached myocytes for topoisomerase IIβ revealed that most of the topoisomerase IIβ was localized to the nucleus, although it was also present in the cytoplasm. Dexrazoxane treatment resulted in an almost complete reduction of topoisomerase IIβ in the nucleus and a lesser reduction in the cytoplasm. The recovery of topoisomerase IIβ levels after a pulse topoisomerase IIβ inhibitory concentration of dexrazoxane occurred slowly, with partial recovery only occurring after 24 h. The ability of dexrazoxane to reduce doxorubicin-induced damage to myocytes was greatest when topoisomerase IIβ levels were at their lowest.
- Effects of Hyperbaric Oxygen Therapy on Acute Myocardial Infarction
Following Carbon Monoxide Poisoning- Abstract: Abstract Carbon monoxide poisoning (COP) may increase the risk of myocardial infarction. We conducted a study to investigate the effects of hyperbaric oxygen therapy (HBOT) on the risk. We used the Nationwide Poisoning Database in Taiwan to identify COP patients diagnosed between 1999 and 2012. We compared the risk for myocardial infarction between patients with and without HBOT by following up through 2013 and identified the independent predictors of myocardial infarction. The risk of myocardial infarction in the 7278 patients with HBOT was lower than in the 18,459 patients without HBOT, but this difference did not reach statistical significance [adjusted hazard ratio (AHR): 0.69; 95% confidence interval (CI) 0.45–1.07]. Stratified analyses showed that the reductions in the risk associated with HBOT for myocardial infarction reached statistical significance in male patients (AHR: 0.45; 95% CI 0.24–0.83) and during the first 2 weeks of follow-up (AHR: 0.22; 95% CI 0.05–0.96). In patients without HBOT, independent predictors of myocardial infarction were old age, male sex, and the underlying comorbidities of hypertension, diabetes, coronary artery disease, and congestive heart failure. In patients with HBOT, however, old age, male sex, and the underlying comorbidities of diabetes, coronary artery disease, and congestive heart failure were not independent predictors. HBOT was associated with a reduced risk of myocardial infarction in male patients and within 2 weeks following COP. These results may provide important reference for using HBOT in treating COP.
PubDate: 2019-11-15
- Abstract: Abstract Carbon monoxide poisoning (COP) may increase the risk of myocardial infarction. We conducted a study to investigate the effects of hyperbaric oxygen therapy (HBOT) on the risk. We used the Nationwide Poisoning Database in Taiwan to identify COP patients diagnosed between 1999 and 2012. We compared the risk for myocardial infarction between patients with and without HBOT by following up through 2013 and identified the independent predictors of myocardial infarction. The risk of myocardial infarction in the 7278 patients with HBOT was lower than in the 18,459 patients without HBOT, but this difference did not reach statistical significance [adjusted hazard ratio (AHR): 0.69; 95% confidence interval (CI) 0.45–1.07]. Stratified analyses showed that the reductions in the risk associated with HBOT for myocardial infarction reached statistical significance in male patients (AHR: 0.45; 95% CI 0.24–0.83) and during the first 2 weeks of follow-up (AHR: 0.22; 95% CI 0.05–0.96). In patients without HBOT, independent predictors of myocardial infarction were old age, male sex, and the underlying comorbidities of hypertension, diabetes, coronary artery disease, and congestive heart failure. In patients with HBOT, however, old age, male sex, and the underlying comorbidities of diabetes, coronary artery disease, and congestive heart failure were not independent predictors. HBOT was associated with a reduced risk of myocardial infarction in male patients and within 2 weeks following COP. These results may provide important reference for using HBOT in treating COP.
- Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role
of Angiotensin 1–7- Abstract: Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1–7 (Ang 1–7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1–7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity. Graphic
PubDate: 2019-11-12
- Abstract: Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1–7 (Ang 1–7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1–7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity. Graphic
