Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.

Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.

[Magnesium orotate in treatment of chronic hypertension in pregnant women].

We examined 150 pregnant women with essential hypertension (EHT), EHT and connective tissue dysplasia (CTD), and healthy. Presence of CTD aggravated clinical picture of EHT and was associated with pronounced cardialgic, neurological, asthenic, vertebrogenic, visceral, and other syndromes. The use of antihypertensive, metabolic (magnesium orotate) drugs, sedative and uroseptic phytotherapy, application of other nondrug measures in conditions of multidisciplinary dynamic support of the gestational period facilitated regress of clinical symptoms of EHT and EHT+CTD, favorable course of pregnancy and successful delivery.

Hypertension in pregnancy: a comprehensive update.

Hypertensive disorders of pregnancies remain a central public health concern throughout the world, and are a major cause of maternal mortality in the developing world. Although treatment options have not significantly changed in recent years, insight on the pathogenesis of preeclampsia/eclampsia has been remarkable. With improved animal models of preeclampsia and large-scale human trials, we have embarked upon a new era where angiogenic biomarkers based on mechanism of disease can be designed to assist in early diagnosis and treatment. There is also a growing recognition of how elusive the diagnosis of eclampsia can be, especially in the postpartum period. Proper treatment of these patients depends heavily on the correct diagnosis, especially by the emergency physician. Finally, large epidemiologic studies have revealed that preeclampsia, once thought to be a self-limited entity, now appears to portend real damage to the cardiovascular and other organ systems in the long term. This review will present the latest update on our understanding of the various hypertensive disorders of pregnancies and their treatment options.

Maternal adaptations to pregnancy in spontaneously hypertensive rats: leptin and ghrelin evaluation.

Leptin and/or ghrelin, initially thought to be considered messengers of energy metabolism, are now considered to play a role in normal and complicated pregnancy. In this study, pregnant, spontaneously hypertensive rats (SHR) have been used to evaluate, for the first time, the modification of leptin and ghrelin both at serum and tissue levels. In SHR, we evaluate plasma leptin level and tissue protein expression in both placenta and adipose tissue at the end of gestation (day 20) versus normotensive Wistar-Kyoto (WKY) animals. The expression of functional leptin receptor (Ob-Rb) in peripheral tissues and in the hypothalamus was evaluated. Moreover, we measured plasma ghrelin level and its mRNA expression in the stomach and placenta. SHR strain presented significantly lower plasma leptin levels when compared with those found in pregnant or not WKY controls. Interestingly, in the placenta, leptin gene expression was higher in SHR than normotensive WKY. Moreover, we demonstrated a resistance to the effects of leptin via 'downregulation' of hypothalamic receptors in pregnant SHR. Conversely, SHR presented significantly higher ghrelin plasma levels when compared with those found in pregnant or not WKY. However, we observed that ghrelin level in the stomach of SHR did not change during pregnancy, and on the opposite, mRNA ghrelin in the placenta of SHR was lower than that of normotensive rats, suggesting a different production of this hormone in the fetal-placental unit. These data gain further insight into metabolic hormone modifications observed in a model of pre-existing hypertension associated with pregnancy.

Influence of calcium intake on gestational hypertension.

Calcium intake during the third trimester of pregnancy was determined in 82 pregnant women by recording the consumption of foods over a 5-day period and by calculation of the quantity of this element provided by dietary supplements. For each subject, blood pressures were measured once per week using an aneroid sphygmomanometer, to detect and analyze differences in calcium intake between those with normal blood pressure and those suffering from gestational hypertension (7.3%). Calcium intake was significantly lower amongst subjects with high blood pressure (757.7 +/- 154.5 compared to 986.4 +/- 502.3 mg/day in normotensive subjects). The relationship between calcium intake and blood pressure was independent of other variables such as body mass index, number of previous pregnancies, weight gain, subject age or hematocrit levels. Though further investigation is needed, the results obtained seem to support the idea that pregnant women should try to maintain an optimal calcium intake.

Aetiopathogenesis of peripartum cardiomyopathy: prolactin-selenium interaction?

The aetiology of peripartum cardiomyopathy is unknown. Fragmentary evidence from the published literature are synthesised to suggest a hypothesis that prolactin-selenium interactions resulting in selenium deficiency and/or autoimmunity are responsible for peripartum cardiomyopathy. This hypothesis best explains the various known facts about the disease. The possible link between prolactin and selenium should be explored.

[Homeostasis of calcium-phosphorus-magnesium in women with pregnancy induced hypertension]. / Homeostaza wapniowo-fosforanowo-magnezowa u kobiet z nadcisnieniem tetniczym krwi indukowanym przez ciaze.

Study group consisted of 63 women in the III trimester of pregnancy (gestational age 29-40 weeks). 32 subjects with PIH (investigated group) were compared to control group consisted of 30 healthy patients with uneventful course of gestation. Women with PIH had no proteinuria nor oedema, their mean blood pressure remained at the level of 161 +/- 16.7/98 +/- 12.8 mm Hg. Concentration of calcium, phosphorus and magnesium in serum blood and urine were determined. It was stated that due to renal impairment observed during PIH, calcium urine excretion and calcium concentration in blood serum are decreased while serum inorganic phosphorus levels are increased. No changes in magnesium and ionised calcium homeostasis were seen in the course of PIH.

Platelet angiotensin II receptor status during pregnancy in Chinese women at high-risk of developing pregnancy-induced hypertension.

OBJECTIVES: The aims of this prospective study were to explore the changes in platelet angiotensin II (A-II) binding in pregnancy amongst Chinese women at high risk of developing pregnancy-induced hypertension (PIH) and the effects of low-dose aspirin and calcium supplementation on A-II binding. METHODS: Platelet A-II binding was assayed in 15 non-pregnant women and in 63 pregnant women determined to be at risk of PIH on the basis of 2nd-trimester mean arterial pressure (MAP). The pregnant patients were randomized into three groups: control, low-dose aspirin, and calcium supplementation. A-II binding was assayed again during the 3rd trimester in half the women and 8 weeks after delivery. RESULTS: A-II binding was negatively correlated with MAP measured in the left lateral position (p < 0.05) but not with MAP measured in the supine position. There were no significant differences between A-II binding in non-pregnant and pregnant women. Neither low-dose aspirin nor calcium supplementation caused significant reductions in A-II binding. CONCLUSION: The measurement of platelet A-II binding is unlikely to provide significant information regarding the risk of PIH over and above that obtained from measurement of 2nd-trimester MAP.

Calcium metabolism in hypertension.

High blood pressure, one of the most common chronic diseases in industrialized societies, is a primary risk factor for cardiovascular disease, heart failure, renal disease and stroke. Data from both epidemiologic surveys and clinical trials have shown that calcium metabolism is altered in persons with hypertension, indicating a primary role of calcium in the etiology, prevention, and treatment of hypertension. Investigative efforts throughout the world have identified abnormalities in a number of biochemical parameters of calcium metabolism and a consistently low intake of dietary calcium in persons with high blood pressure. Calcium supplementation trials have reported varying results in terms blood pressure response, and it is generally concluded that many hypertensive patients may benefit from increased calcium intake. The blood pressure-lowering effect of calcium may be of particular benefit to the elderly, people of African origin, and pregnant women. Interactions between dietary nutrients have been shown to be critical in the effect of calcium on blood pressure, particularly sodium and potassium. Finally, based on the body of data that has accumulated in this area, calcium intake is postulated to have clinical application in the treatment of sodium-sensitive, alcohol-associated, and pregnancy-induced hypertension, and type II diabetes mellitus; and adequate, long-term calcium intake may be a means of preventing the development of hypertension.

Calcium metabolism in normal and hypertensive pregnancy.

Calcium homeostasis is an important aspect of maternal and fetal physiology during gestation, and recent evidence implicates alterations in calcium metabolism in the pathogenesis of hypertension during pregnancy. Deficiencies in calcium intake have been linked to preeclampsia/eclampsia, and hypocalciuria and deviations in both 1,25(OH)2D3 and PTH have been shown in women with preeclampsia. Preliminary studies also suggest that calcium supplementation may lower blood pressure and prevent preeclampsia in pregnant women.

Calcium metabolism, calcium supplementation and hypertensive disorders of pregnancy.

In recent years growing attention has been directed towards the possible role of calcium in the development of pregnancy-induced hypertension and preeclampsia. Several studies describe calcium metabolism in normal and hypertensive pregnancy, but so far, they have shown discrepant and inconsistent results. Intracellular free calcium, which plays an important role in vascular smooth muscle contraction, has been claimed as a pathogenic factor in hypertensive disorders of pregnancy. Although there is discordance in the data, a possible role of intracellular calcium in the development of hypertensive disorders of pregnancy cannot be excluded. Observational studies in pregnant women suggest an inverse association between calcium intake and the incidence of hypertensive disorders of pregnancy. Despite large methodological differences, the results from the calcium supplementation trials support this finding. Although it is rather difficult to isolate the effect of calcium intake from the intake of other mineral elements, results from calcium supplementation trials are supportive for calcium being the most important. Proposed mechanisms by which calcium supplementation may lower blood pressure involve changes in parathyroid hormone (PTH) level, the renin-angiotensin system and calcium as a modifier of vascular agent regulation, but none of these have yet been elucidated. At present, circumstantial evidence suggest a positive role for calcium in the prevention of hypertensive disorders of pregnancy, but definite evidence is lacking and further research is warranted.

Calcium homeostasis in pregnancy during long-term heparin treatment.

OBJECTIVE: To investigate the effect of subcutaneous heparin treatment on calcium homeostasis in pregnancy. DESIGN: A longitudinal case-control observational study. SETTING: Department of Obstetrics and Gynaecology, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: 36 pregnant women with previously verified thromboembolic complications and 23 healthy pregnant control women similar in age, parity, weight, and smoking habit. INTERVENTIONS: Thromboprophylaxis during pregnancy and 6 weeks post partum was given with subcutaneous heparin twice daily to the 36 women with a history of thromboembolic complications, 16 received an average dose of 24,500 IU/day and 20 a mean dose of 17,300 IU/day. Venous blood and urine samples were obtained every 4 weeks. MAIN OUTCOME MEASURES: Serum concentrations of total calcium, ionized calcium, calcitonin and urinary calcium. RESULTS: Women on high-dose heparin treatment showed significantly higher concentrations of total and ionized calcium and of calcitonin in serum and significantly lower concentrations of calcium in urine than did 23 normal pregnant controls. The differences were most pronounced in the third trimester. The results obtained in the low-dose heparin group were between those in the high-dose and the control groups. At 8 weeks postpartum there were no significant differences between the heparin-treated women and the controls. No significant differences were found during pregnancy in haematocrit, liver or renal function, serum levels of albumin, phosphate, magnesium, alkaline phosphatase, parathyroid hormone or urinary cyclic AMP. CONCLUSIONS: Heparin treatment during pregnancy results in changes in calcium homeostasis and a dose-dependent response is suggested.

Magnesium supplement in pregnancy-induced hypertension: effects on maternal and neonatal magnesium and calcium homeostasis.

The objective of this study was to evaluate the effect of low dose magnesium supplement upon maternal and fetal serum levels of mineral status in pregnancies complicated with hypertension (PIH). Twenty-five patients with PIH agreed to participate and were randomly allocated, in a double-blind manner, either to intravenous magnesium for 2 days followed by oral magnesium (n = 12) until delivery or placebo (n = 13). In women supplemented with magnesium the level of magnesium increased from 0.74 to 1.02 mmol/l during the first 24 h of inclusion and simultaneously we observed an increased urinary loss of magnesium. Serum level and the urinary excretion of magnesium returned to pretreatment level at delivery. Maternal magnesium supplement increased the concentrations of magnesium in umbilical cord and neonatal blood 1 day after delivery. Serum ionized calcium did not change during the study period despite a significant increased loss of calcium during the first 24 h of inclusion. Low dose maternal magnesium treatment did not cause neonatal hypocalcemia.

Prevention of toxemia of pregnancy in Ecuadorian Andean women: experience with dietary calcium supplementation.

Pregnancy-induced hypertension (PIH) is a significant cause of low birth weight and maternal and neonatal death around the world. This article reviews work indicating that dietary calcium supplementation can sharply reduce the PIH incidence among pregnant women whose regular diet is calcium-poor. It also describes physiologic conditions prevailing during pregnancy that could explain calcium's major role in PIH--as well as supplemental calcium's great potential for preventing PIH among people with low-calcium diets.

[Dynamics of calcium metabolism and calcium-regulating hormones in pregnancy-induced hypertension].

Serum concentrations of total calcium, ionized calcium and inorganic phosphorus in severe PIH were significantly lower than those in normal pregnancy during the 3rd trimester of pregnancy and continued to be low even at puerperium. On the other hand, serum concentrations of parathyroid hormone in severe PIH were significantly higher during the 3rd trimester of pregnancy and decreased at puerperium. Any remarkable differences in serum calcitonin levels were not found between severe PIH and normal pregnancy through the last trimester of pregnancy and puerperium. Serum concentrations of 1 alpha, 25-(OH)2 vitamin D3 increased significantly in the 3rd trimester of normal pregnancy, but in severe PIH, their increase was not observed, remaining at the normal levels of non-pregnant women. The kidney functions in the both groups were within the normal limits of non-pregnant women, but placental dysfunction was observed in severe PIH. These results suggest that the decrease in serum calcium and phosphorus levels might have occurred as a result of the decrease in the absorption of calcium and phosphorus from the intestine due to the decrease in serum 1 alpha, 25-(OH)2 vitamin D3 levels and that low serum 1 alpha, 25-(OH)2 vitamin D3 concentrations might be caused by the disturbance of the synthesis in the placenta rather than in the kidney.