Age-related regulation of excitation–contraction coupling in rat heart

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Hearts from subjects with different ages have different Ca2+ signaling. Release of Ca2+ from intracellular stores in response to an action potential initiates cardiac contraction. Both depolarization-stimulated and spontaneous Ca2+ releases, Ca2+ transients and Ca2+ sparks, demonstrate the main events of excitation–contraction coupling (ECC). Global increase in free Ca2+concentration ([Ca2+] i ) consists of summation of Ca2+ release events in cardiomyocytes. Since the Ca2+ flux induced by Ca2+ sparks reports a summation of ryanodine-sensitive Ca2+ release channels (RyR2s)’s behavior in a spark cluster, evaluation of the properties of Ca2+ sparks and Ca2+ transients may provide insight into the role of RyR2s on altered heart function between 3-month-old (young adult) and 6-month-old (mature adult) rats. Basal [Ca2+] i and Ca2+ sparks frequency were significantly higher in mature adult rats compared to those of young adults. Moreover, amplitudes of Ca2+ sparks and Ca2+ transients were significantly smaller in mature adults than those of young adults with longer time courses. A smaller L-type Ca2+ current density and decreased SR Ca2+ load was observed in mature adult rats. In addition, RyR2s were markedly hyperphosphorylated, and phosphorylation levels of PKA and CaMKII were higher in heart from mature adults compared to those of young adults, whereas their SERCA protein levels were similar. Our data demonstrate that hearts from rats with different ages have different Ca2+ signaling including hyperphosphorylation of RyR2s and higher basal [Ca2+] i together with increased oxidized protein-thiols in mature adult rats compared to those of young adults, which play important roles in ECC. Finally, we report that ECC efficiency changes with age during maturation, partially related with an increased cellular oxidation level leading to reduced free protein-thiols in cardiomyocytes (AU)

Profound cardioprotection with timolol in a female rat model of aging-related altered left ventricular function.

Increasing evidence shows a marked beneficial effect with ß-blockers in heart dysfunction via scavenging reactive oxygen species. Previously we showed that chronic treatment with either timolol or propranolol possessed similar beneficial effects for heart function in male rats as age increased, whereas only timolol exerted similar benefits in female rats. Therefore, in this study, we aimed first to examine the cellular bases for age-related alterations in excitation-contraction coupling in ventricular myocytes from female rats and, second, to investigate the hypothesis that age-related changes in [Ca(2+)](i) homeostasis and receptor-mediated system can be prevented with chronic timolol treatment. Chronic timolol treatment of 3-month-old female rats abolished age-related decrease in left ventricular developed pressure and the attenuated responses to ß-adrenoreceptor stimulation. It also normalized the altered parameters of [Ca(2+)](i) transients, decreased Ca(2+) loading of sarcoplasmic reticulum and increased basal [Ca(2+)](i), and decreased L-type Ca(2+) currents in 12-month-old female rats compared with the 3-month-old group. Adenylyl cyclase activity, ß-adrenoreceptor affinity to its agonist, and ß-adrenoreceptor density of the 12-month-old group are normalized to those of the 3-month-old group. Moreover, timolol treatment prevented dysfunction of the antioxidant system, including increased lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and decreased activities of thioredoxin reductase and glucose-6-phosphate dehydrogenase, in the left ventricle of hearts from the 12-month-old group. Our data confirmed that aging-related early myocardial impairment is primarily related to a dysfunctional antioxidant system and impairment of Ca(2+) homeostasis, which can be prevented with chronic timolol treatment.

Age-related regulation of excitation-contraction coupling in rat heart.

Hearts from subjects with different ages have different Ca(2+) signaling. Release of Ca(2+) from intracellular stores in response to an action potential initiates cardiac contraction. Both depolarization-stimulated and spontaneous Ca(2+) releases, Ca(2+) transients and Ca(2+) sparks, demonstrate the main events of excitation-contraction coupling (ECC). Global increase in free Ca(2+) concentration ([Ca(2+)]( i )) consists of summation of Ca(2+) release events in cardiomyocytes. Since the Ca(2+) flux induced by Ca(2+) sparks reports a summation of ryanodine-sensitive Ca(2+) release channels (RyR2s)'s behavior in a spark cluster, evaluation of the properties of Ca(2+) sparks and Ca(2+) transients may provide insight into the role of RyR2s on altered heart function between 3-month-old (young adult) and 6-month-old (mature adult) rats. Basal [Ca(2+)]( i ) and Ca(2+) sparks frequency were significantly higher in mature adult rats compared to those of young adults. Moreover, amplitudes of Ca(2+) sparks and Ca(2+) transients were significantly smaller in mature adults than those of young adults with longer time courses. A smaller L-type Ca(2+) current density and decreased SR Ca(2+) load was observed in mature adult rats. In addition, RyR2s were markedly hyperphosphorylated, and phosphorylation levels of PKA and CaMKII were higher in heart from mature adults compared to those of young adults, whereas their SERCA protein levels were similar. Our data demonstrate that hearts from rats with different ages have different Ca(2+) signaling including hyperphosphorylation of RyR2s and higher basal [Ca(2+)]( i ) together with increased oxidized protein-thiols in mature adult rats compared to those of young adults, which play important roles in ECC. Finally, we report that ECC efficiency changes with age during maturation, partially related with an increased cellular oxidation level leading to reduced free protein-thiols in cardiomyocytes.

Intracellular free zinc during cardiac excitation-contraction cycle: calcium and redox dependencies.

AIMS: Zinc exists in biological systems as bound and histochemically reactive free Zn(2+). It is an essential structural constituent of many proteins, including enzymes from cellular signalling pathways, in which it functions as a signalling molecule. In cardiomyocytes at rest, Zn(2+) concentration is in the nanomolar range. Very little is known about precise mechanisms controlling the intracellular distribution of Zn(2+) and its variations during cardiac function. METHODS AND RESULTS: Live-cell detection of intracellular Zn(2+) has become feasible through the recent development of Zn(2+)-sensitive and -selective fluorophores able to distinguish Zn(2+) from Ca(2+). Here, in freshly isolated rat cardiomyocytes, we investigated the rapid changes in Zn(2+) homeostasis using the Zn(2+)-specific fluorescent dye, FluoZin-3, in comparison to Ca(2+)-dependent fluo-3 fluorescence. Zn(2+) sparks and Zn(2+) transients, in quiescent and electrically stimulated cardiomyocytes, respectively, were visualized in a similar manner to known rapid Ca(2+) changes. Both Zn(2+) sparks and Zn(2+) transients required Ca(2+) entry. Inhibiting the sarcoplasmic reticulum Ca(2+) release or increasing the Ca(2+) load in a low-Na(+) solution suppressed or increased Zn(2+) movements, respectively. Mitochondrial inhibitors slightly reduced both Zn(2+) sparks and Zn(2+) transients. Oxidation by H2O2 facilitated and acidic pH inhibited the Ca(2+)-dependent Zn(2+) release. CONCLUSION: It is proposed that Zn(2+) release during the cardiac cycle results mostly from intracellular free Ca(2+) increase, triggering production of reactive oxygen species that induce changes in metal-binding properties of metallothioneins and other redox-active proteins, aside from ionic exchange on these proteins.

Novel derivatives of 1,3,4-oxadiazoles are potent mitostatic agents featuring strong microtubule depolymerizing activity in the sea urchin embryo and cell culture assays.

A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site.

Advanced age is associated with endothelial dysfunction in healthy elderly subjects.

BACKGROUND: Aging is associated with an increased risk for atherosclerosis in which endothelial dysfunction is an early marker. OBJECTIVE: The purpose of this study was to determine if endothelial function is altered with increasing age in healthy subjects. METHOD: The study population consisted of 30 elderly and 36 younger subjects free from major cardiovascular risk factors. Transthoracic echocardiography was performed for each subject to rule out structural heart disease. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery via ultrasound. RESULTS: Baseline characteristics of the elderly and the younger group were similar, except for age (mean age: 71.3 +/- 5.8 vs. 26.5 +/- 7.2). Transthoracic echocardiography was normal in all subjects. FMD of the elderly group was significantly lower than the younger group (7.9 +/- 3.1 in the elderly, 10.8 +/- 1.9 in the younger group, p < 0.001). A negative relationship was found between FMD and age (r = -0.528, p < 0.001). CONCLUSION: It can be concluded that endothelial function detected by FMD declines with increasing age in healthy human subjects. Advanced age is a predictor of impaired endothelial function.

Determining the relationship between metabolic syndrome score and angiographic severity of coronary artery disease.

BACKGROUND: Cardiovascular disease is leading cause of mortality and morbidity in developed and developing countries. Metabolic syndrome (MS) is a risk factor for coronary artery disease (CAD). The effect of MS on angiographic severity of CAD is not well defined. The aim of this study was to examine the effect of MS on angiographic severity of CAD by using Gensini score. METHODS: The total number of 1003 patients who underwent elective coronary angiography in catheter laboratory were included in the study. MS score based on National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria which ranged between zero and five were calculated for each subject. Gensini scores were determined by examining coronary angiograms of the patients. RESULTS: The study population consisted of 634 (63%) male, and 369 (37%) female subjects. The mean age was 59 +/- 11. MS based on NCEP ATP III was present in 246 (25%) patients. CAD was present in 691 patients (69%). The median of Gensini score was five (0-192) in the total sample, 18 (1-192) in the patients with CAD and 25 (0-192) in the patients with MS. A positive correlation was found between MS score and Gensini score (r = 0.402, p < 0.001). CONCLUSIONS: In this study, it was determined that as the severity of MS increases, the angiographic severity of CAD increases as well. Besides, the most important factor on Gensini score was diabetes mellitus in male and hypertension in female subjects.

Percutaneous balloon pericardiotomy for patients with malignant pericardial effusion including three malignant pleural mesotheliomas.

Ten patients were enrolled in this study to evaluate the therapeutic value of percutaneous balloon pericardiotomy in patients with symptomatic pericardial effusion secondary to malignant diseases. Four patients had breast cancer; 2 had lung cancer; 1 had non-Hodgkin's lymphoma; and 3 had malignant pleural mesothelioma, which is commonly seen in Central Anatolian region of Turkey. All patients underwent percutaneous balloon pericardiotomy with monofoil balloons (Mansfield, NuMed). No complication was seen during these procedures. In 3 patients, the balloon could not be expanded completely and was entered from a more lateral position by a second puncture. There was no recurrence of pericardial effusion in 6 of 7 patients without mesothelioma. After percutaneous balloon pericardiotomy, surgical subxiphoid windowing was performed due to drainage greater than 100 mL/day in a patient with lung cancer and in 1 patient with mesothelioma. In the other 2 patients with mesothelioma, recurrence of pericardial effusion was seen and then subxiphoid surgical windowing was performed due to development of cardiac tamponade in 1 of them. All the patients died 68.6 +/- 36 days later due to the primary malignancies. The survival time of patients with mesothelioma was shorter than that of the others (p < 0.05). These results suggest that percutaneous balloon pericardiotomy may be used in the treatment of patients with malignant pericardial effusion as an alternative to surgical pericardial window creation. But in patients with malignant pleural mesothelioma, the success rate of this procedure was lower than that of the others.

QT dispersion as a predictor of arrhythmic events in patients with ankylosing spondylitis.

OBJECTIVE: The aim of the study was to evaluate QT dispersion (QTd), an indicator of repolarization heterogeneity, and its relation to ventricular arrhythmias in patients with ankylosing spondylitis (AS). METHODS: A full history, clinical examination, electrocardiograms and 24-h Holter monitoring were performed in 88 AS patients and 31 volunteers of similar age and sex. Groups were compared based on electrocardiographic abnormality, QTd, arrhythmias and heart blocks. RESULTS: QTd and corrected QTd (QTcd) were significantly greater in AS patients than controls (QTd, 52.8 +/- 15.1 vs 35.5 +/- 8.9 ms, P: < 0.0001; QTcd, 60.3 +/- 16.1 vs 39.4 +/- 10.7 ms, P: < 0.0001). The magnitudes of these parameters were associated with the duration of the disease (QTd, r = 0.56, P: < 0.01; QTcd, r = 0.60, P: < 0.001). The frequency of ventricular extrasystoles was found to be correlated with QTd (r = 0.35, P: < 0.01) and QTcd (r = 0.33, P: < 0. 01). CONCLUSION: Involvement of the heart may be seen in AS during the early clinical course of the disease. QTd may give clues about the presence of arrhythmias and can be used as a new technique for the evaluation of asymptomatic patients. Earlier detection of cardiac involvement could alter the prognosis of the patients.

Is ventricular repolarization heterogeneity a cause of serious ventricular tachyarrhythmias in aortic valve stenosis?

BACKGROUND: It is well known that there is a close relation between sudden cardiac death and serious ventricular tachyarrhythmias in patients with aortic valve stenosis (AS). QT dispersion (QTd) reflects the ventricular repolarization heterogeneity and has been proposed as an indicator for ventricular arrhythmias. HYPOTHESIS: This study investigated the QTd and its relevance to the clinical and echocardiographic variables. METHODS: In all, 51 patients (33 men, 18 women, mean age 56 +/- 12) with isolated AS and 51 age- and gender-matched healthy controls comprised the study group. Left ventricular mass index (LVMI) was calculated by the Devereux formula, and we used continuous-wave Doppler (n = 15) and cardiac catheterization (n = 36) for the determination of the maximum aortic valve pressure gradient (PG). RESULTS: Corrected QTd (QTcd) (89 +/- 39 vs. 49 +/- 15 ms, p < 0.001) and LVMI (176 +/- 69 g/m2 vs. 101 +/- 28 g/m2, p < 0.001) in patients with AS were significantly different from those in the control group. The group of 21 patients had a significantly greater number of 24-h mean ventricular premature beats (VPB) and mean number of couplet VT episodes than did the control group (p < 0.05). QTcd also correlated significantly well with LVMI (r = 0.58, p < 0.001), PG (r = 0.41, p = 0.003), and number of 24-h VPB (r = 0.56, p = 0.008). With respect to symptoms (e.g., angina, syncope, and dyspnea) patients without symptoms (n = 19) displayed less QTcd (71 +/- 31 vs. 100 +/- 39 ms, p = 0.007) and less LVMI (144 +/- 80 g/m2 vs. 195 +/- 57 g/m2, p = 0.01) than patients with symptoms. Statistical analysis was similar for all variables with uncorrected QTd values. CONCLUSION: We found that ventricular repolarization heterogeneity was greater in patients with AS than in controls. Our findings also showed that QTd in the patient group correlates well with LVMI, severity of AS, and PG. The present results suggest that serious ventricular arrhythmias in patients with AS may be due to spatial ventricular repolarization abnormality.

Blood cyst originating from tricuspid septal leaflet.

Successful removal of a blood cyst of the tricuspid valve in a 34 years old man is reported. The rarity of this cyst in an adult and diagnostic clues are discussed.

Pregnancy and its complications after cardiac valve replacement.

The outcome of 64 pregnancies in 40 women who conceived after cardiac valve replacement were reviewed. Fetal wastage was 53.2% (25/47) in coumarin administered pregnancies, 36.4% (4/11) using heparin and 16.7% (1/6) without anticoagulants. Two fetal malformations were noted in coumarin administered pregnancies. There were two maternal deaths. Maternal morbidity due to antenatal bleeding, atrial fibrillation, thromboembolic episodes and cardiac failure were found to be 20.0% (8/40), 17.5% (7/40), 10.0% (4/40) and 10.0% (4/40), respectively.

Iliac artery aneurysm in Behçet's disease: a case report.

Today, Behcet's disease is known as a multisystem disorder. Eye lesions, mouth and genital aphthous lesions, and skin lesions are accepted as major lesions. The disease also attacks the locomotor system, central nervous system, gastrointestinal system and also arteries and veins. According to available data, some 30% of the patients have vascular lesions; mostly thrombosis of the veins. Arterial thromboses have been rarely reported; and only a few number of arterial aneurysms are noted. Here we present an iliac artery aneurysm in a case of Behcet's disease.