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![In aldosteronism (ALDOST), where plasma aldosterone levels are inappropriately elevated relative to dietary Na þ intake, marked excretory losses of Ca 2þ and Mg 2þ lead to a fall in their plasma ionized concentrations. Reduced [Ca 2þ ] o and [Mg 2þ ] o are, respectively, major and minor stimuli to the parathyroid glands' secretion of parathyroid hormone (PTH), with secondary hyperparathyroidism (SHPT) accounting for bone resorption in an attempt to restore the homeostasis of these divalent cations. In what is coined as a calcium paradox, elevations in plasma PTH promote intracellular Ca 2þ overloading and induction of oxidative stress. Reactive oxygen species (ROS) and peroxynitrite (OONO 2 ) contribute to intracellular signalling that, in a concentration-dependent manner, eventuates in cell activation (e.g. peripheral blood mononuclear cells, PBMC) and the expression of apoptotic and necrotic cell death pathways in cardiomyocytes. Urinary and faecal losses of Zn are likewise increased during ALDOST (data not shown). A high (8%) Na þ diet, which suppresses plasma aldosterone levels, also leads to SHPT because of increased excretory losses of Ca 2þ .](profile/Karl-Weber-7/publication/23300369/figure/fig1/AS:601644085542921@1520454536672/n-aldosteronism-ALDOST-where-plasma-aldosterone-levels-are-inappropriately-elevated.png)
In aldosteronism (ALDOST), where plasma aldosterone levels are inappropriately elevated relative to dietary Na þ intake, marked excretory losses of Ca 2þ and Mg 2þ lead to a fall in their plasma ionized concentrations. Reduced [Ca 2þ ] o and [Mg 2þ ] o are, respectively, major and minor stimuli to the parathyroid glands' secretion of parathyroid hormone (PTH), with secondary hyperparathyroidism (SHPT) accounting for bone resorption in an attempt to restore the homeostasis of these divalent cations. In what is coined as a calcium paradox, elevations in plasma PTH promote intracellular Ca 2þ overloading and induction of oxidative stress. Reactive oxygen species (ROS) and peroxynitrite (OONO 2 ) contribute to intracellular signalling that, in a concentration-dependent manner, eventuates in cell activation (e.g. peripheral blood mononuclear cells, PBMC) and the expression of apoptotic and necrotic cell death pathways in cardiomyocytes. Urinary and faecal losses of Zn are likewise increased during ALDOST (data not shown). A high (8%) Na þ diet, which suppresses plasma aldosterone levels, also leads to SHPT because of increased excretory losses of Ca 2þ .
Source publication
Hypertension and heart failure are worldwide health problems of ever-increasing proportions. A failure of the heart, during either systolic and/or diastolic phases of the cardiac cycle, has its origins rooted in an adverse structural, biochemical, and molecular remodelling of myocardium that involves its cellular constituents, extracellular matrix,...
Contexts in source publication
Context 1
... aldosteronism, an integral feature of CHF and some forms of hypertension, intracellular Ca 2þ overloading of diverse tissues occurs invariably and is PTH-mediated. As shown in Figure 1, elevations in circulating PTH occur in response to ionized hypocalcaemia and hypomagnesaemia caused by the heightened urinary and faecal excretion of Ca 2þ and Mg 2þ that accompanies aldosterone/1% NaCl treat- ment (ALDOST). [21][22][23][24][25][26][27] SHPT is invoked during ALDOST to restore extracellular Ca 2þ and Mg 2þ homeostasis through bone resorption, 28 and increased Ca 2þ resorption from the kidney and gastrointestinal tract. ...
Context 2
... important role of PTH-mediated intracellular Ca 2þ overloading is further evi- denced by the hypertension, left ventricular hypertrophy, and adverse structural remodelling of myocardium, as well as myocardial and valvular calcification, arrhythmia and abnormal conduction, and altered vasomotor reactivity with vascular remodelling found in primary hyperparathyroid- ism. 29,30 A high-Na þ diet (8%), which suppresses plasma aldos- terone levels, is calciuric in rats and man, and like ALDOST it also leads to SHPT with PTH-mediated bone resorption and intracellular Ca 2þ overloading ( Figure 1). 27,31,32 Low-renin hypertension is also accompanied by ionized hypocalcaemia, increased plasma PTH with elevations in platelet [Ca 2þ ] i , and a favourable reduction in elevated blood pressure to dietary Ca 2þ supplement or Ca 2þ channel blocker. ...
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Citations
... In TM, vitamin D can affect myocardial size and function not only indirectly by influencing cardiac iron uptake but also directly. The direct effects of vitamin D on the myocardium include a reduction in cardiomyocyte hypertrophy by the downregulation of specific genes [71], modulation of the renin-angiotensin system (RAS), which plays a key role in the regulation of volume and blood pressure homeostasis [72,73], moderation of extracellular matrix production and deposition in myocardial tissue [74], nongenomic and genomic influences on cardiac contractility and intracellular calcium regulation, and regulation of myosin expression and heart energy metabolism [75,76]. ...
We evaluated the association of vitamin D and parathormone (PTH) levels with cardiac iron and function in beta-thalassemia major (β-TM) patients. Two-hundred and seventy-eight TM patients (39.04 ± 8.58 years, 56.8% females) underwent magnetic resonance imaging for the assessment of iron overload (T2* technique), biventricular function parameters (cine images), and replacement myocardial fibrosis (late gadolinium enhancement technique). Vitamin D levels were deficient (<20 ng/dL) in 107 (38.5%) patients, insufficient (20–30 ng/dL) in 96 (34.5%) patients, and sufficient (≥30 ng/dL) in 75 (27.0%) patients. Deficient vitamin D patients had a significantly higher frequency of myocardial iron overload (MIO; global heart T2* < 20 ms) than patients with sufficient and insufficient vitamin D levels and a significantly higher left ventricular end-diastolic volume index and mass index than patients with sufficient vitamin D levels. PTH was not associated with cardiac iron, function, or fibrosis. In the multivariate regression analysis, vitamin D, serum ferritin, and pancreatic iron levels were the strongest predictors of global heart T2* values. In receiver operating characteristic curve analysis, a vitamin D level ≤ 17.3 ng/dL predicted MIO with a sensitivity of 81.5% and a specificity of 75.3% (p < 0.0001). In TM, the periodic and regular assessment of vitamin D levels can be beneficial for the prevention of cardiac iron accumulation and subsequent overt dysfunction.
... There is an association between zinc deficiency and various health abnormalities, including aging through its levels not only in the whole body but also in cellular levels (Chasapis et al. 2012). In this regard, experimental studies have shown that the extracellular and dyshomeostasis in intracellular levels of free zinc ion ([Zn 2+ ] i ) are also related to cardiovascular health besides others (Turan et al. 1997;Weber et al. 2009;Foster and Samman 2010;Xu and Zhou 2013;Olgar et al. 2018Olgar et al. , 2019Turan 2019). However, there are conflicting reports on this topic in the literature, particularly associated with clinical results, such as opposite findings associated with a relationship between body zinc levels and heart failure (Shokrzadeh et al. 2009;Yu et al. 2018). ...
... Clinical data emphasize a relationship between low serum zinc levels and disease states in humans (Prasad 1983;Ripa et al. 1998;Eby and Halcomb 2006;Ghaemian et al. 2011;Choi et al. 2018;Rosenblum et al. 2020). However, there are also some studies demonstrating the importance of excessive zinc intake and its toxic effects, particularly in both clinical and experimental studies with heart preparations (Turan et al. 1997;Ayaz and Turan 2006;Eby and Halcomb 2006;Weber et al. 2009;Foster and Samman 2010;Little et al. 2010;Islamoglu et al. 2011;Xu and Zhou 2013;Efeovbokhan et al. 2014;Olgar et al. 2018Olgar et al. , 2019Turan 2019). The cellular free Zn 2+ level ([Zn 2+ ] i ) and Zn 2+ signaling are controlled mainly by Zn 2+ -transporters (Eide 2006;Hara et al. 2017;Kambe et al. 2021). ...
Intracellular free Zn²⁺ ([Zn²⁺]i) is less than 1-nM in cardiomyocytes and its regulation is performed with Zn²⁺-transporters. However, the roles of Zn²⁺-transporters in cardiomyocytes are not defined exactly yet. Here, we aimed to examine the role of an overexpression and subcellular localization of a ZnT6 in insulin-resistance mimic H9c2 cardiomyoblasts (IR-cells; 50-μM palmitic acid for 24-h incubation). We used both IR-cells and ZnT6-overexpressed (ZnT6OE) cells in comparison to those of H9c2 cells (CON-cells). The IR-cells have higher ZnT6-protein levels than CON-cells while this level was similar to those of ZnT6OE-cells. The [Zn²⁺]i in IR-cells was increased significantly and mitochondrial localization of ZnT6 was demonstrated in these cells by using confocal microscopy visualization. Furthermore, electron microscopy analysis demonstrated abnormal morphological appearance in both IR-cells and ZnT6OE-cells characterized by irregular mitochondrion cristae and condensed and dilated cisterna in the sarcoplasmic reticulum. Mitochondria were similarly depolarized in both IR-cells and ZnT6OE-cells. The protein expression level of a mitofusin protein MFN2 in the IR-cells was decreased, significantly, whereas, it was found significantly upregulated in both ZnT6-OE-cells and IR-incubated ZnT6OE-cells, which demonstrates the role of ZnT6-overexpression but not IR. Additionally, the total protein level of a mitochondrial fission protein, dynamin-related protein 1, DRP1 was found to be increased over 1.5-fold in IR-cells while this increase was found to be higher in the ZnT6OE-cells than those of IR-cells, demonstrating an additional effect on IR-increase. ZnT6-overexpression induced also significant increases in K-acetylation, trimethylation of histone H3 lysine27, and mono-methylation of histone H3 lysine36, in a similar manner to those of IR-cells. Overall, our data point out an important contribution of ZnT6-overexpression to IR-induced cellular changes, such as alteration in mitochondria function and activation of epigenetic modifications.
... Accumulation of free oxygen radicals increases pro-inflammatory cytokines, such as TNF-alpha, IL-1 and IL-6, which causes cardiomyocyte death and intensifies cardiac dysfunction. The maladaptive process of replacing necrotic myocytes results also in cardiac fibrosis [22,23]. In vitro studies have linked hypovitaminosis D with elevated TNF-α levels and decreased IL-10 concentrations, suggesting an immunomodulatory effect and anti-inflammatory response of vitamin D. Furthermore, it is known that hypovitaminosis D causes hypocalcemia that stimulates parathyroid hormone secretion, another risk factor currently investigated for its involvement in cardiovascular diseases [24][25][26]. ...
Background: Several studies in recent years have shown the association between vitamin D levels and heart failure. Vitamin D deficiency is related to increased cardiovascular morbidity and mortality, with a higher risk of developing heart failure. In this systematic review, we aimed to assess recent studies that analyzed vitamin D deficiency and heart failure in adult and pediatric populations. (2) Methods: We conducted a systematic search for studies published in the following databases: PubMed and Scopus from January 2012 to October 2022. (3) Results: Most observational studies that were included found a significant association between hypovitaminosis D and heart failure. However, the beneficial role of vitamin D supplementation is still controversial due to the lack of randomized controlled trials. (4) Conclusions: Vitamin D may play an important role as a cardiovascular marker in heart failure patients. More well-designed studies are needed to investigate the relationship between vitamin D and heart failure and to determine if vitamin D supplementation could improve long-term outcomes.
... The high percentage of overweight and obese participants observed in this study may be a reflection of poor eating habits and low physical activity, affecting equally men and women (Refer to Table 1). In our study, patients with HF in III-IV class of NYHA showed positive correlations between CH, LDL, TG levels and the presence of diabetes and arterial hypertension (Refer to Table 12), which is in agreement with reports from other authors (Weber, Weglicki & Simpson, 2009). Interestingly, some 80% of the studied patients who were found to have macro-and micromineral deficiencies were also obese (with abnormally high BMI scores). ...
... In the literature, it was demonstrated that alterations in the concentrations of both macro-and microminerals may impact on heart failure (Sattler et al., 2019;Weber, Weglicki & Simpson, 2009). Disturbed mineral homeostasis in serum, related to the development and progression of HF, may contribute to adverse structural remodelling of the heart and affect its function. ...
... In turn, about 50% of the participants presented increased Ca concentrations, correlated with the levels of Mg, Ca/Mg, Fe, Zn in both groups 1 and 2 (Refer to Tables 11 and 12). In the literature, increases in calcium ions were reported in response to oxidative stress and in cardiomyocyte necrosis (Weber, Weglicki & Simpson, 2009). In heart failure, alterations in Fe levels, including depletion, are some of the most common coexisting symptoms, potentially affecting 37-61% of patients Enjuanes et al., 2016). ...
Background
The study investigated the relationship between the concentrations of Mg, Ca, Fe, Cu, Zn, P and anthropometric and biochemical parameters in the blood serum of patients with heart failure (HF) and the potential influence on the development and progression of HF.
Material & methods
The study included 214 patients (155 men and 59 women), aged 40–87 years, presenting symptoms or signs typical of HF (according to the NYHA functional classification). Serum concentrations were determined for Mg, Ca, Fe, Cu, Zn, P, C-reactive protein (CRP), creatinine, urea, triglyceride levels (TG), total cholesterol (CH), high density protein (HDL), low density protein (LDL). The levels of macro-and microminerals were analysed using inductively coupled serum optical emission spectrometry (ICP-OES).
Results
Our study confirmed the role of known risk factors in the development of heart failure, including: overweight, diabetes, hypertension, high triglycerides (TG), high total cholesterol (CH), high levels of low density protein (LDL) and reduced levels of high density protein (HDL), high CRP, high creatinine. Moreover, deficient serum concentrations of Mg (47% of the studied men and 54% of the women) and Cu (in 44% of men and more than 30% of women) were observed, as well as subnormal serum Fe (2% of women) and Zn (1% of men). Elevated serum Ca was found in 50% of men and 49% of women. In 44% of the studied men and 52% of the studied women, P levels in serum were also above-average. The study revealed a significant positive correlation between serum levels of Ca and Mg, and also Ca and Cu in women. In men, serum Cu was positively correlated with Mg and Ca concentrations. In patients from group 1 (NYHA I–II), Mg content was positively correlated with Ca and Cu. In this patient group, Ca was also positively associated with Cu content in serum. In group 2 (NYHA III-IV), serum Mg concentration was significantly positively correlated with that of Cu and Ca.
Conclusions
Changes in the serum concentrations of macro-and microminerals may significantly affect the severity of HF in Polish patients.
... VDR activity also contributes to cardiac fibrosis and extracellular matrix remodel through the regulation of the expression of ECM mediators such as matrix metallop teinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) [254]. Lack of VDR duces myocardial expression of MMP-2 and MMP9 and dampens myocardial TIMP-1 a TIMP-3 expression, correlating with cellular hypertrophy and cardiac fibrosis [76]. ...
... VDR activity also contributes to cardiac fibrosis and extracellular matrix remodeling through the regulation of the expression of ECM mediators such as matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) [254]. Lack of VDR induces myocardial expression of MMP-2 and MMP9 and dampens myocardial TIMP-1 and TIMP-3 expression, correlating with cellular hypertrophy and cardiac fibrosis [76]. ...
The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.
... The association between zinc deficiency and dilated cardiomyopathy is well documented [45,59,60,[71][72][73]. Urinary concentrations of Zn in subjects with DCM was 4 times the reference value denoting very high excretion [47], a commonly noted phenomenon during heart failure. ...
Blood and/or urine levels of 27 heavy metals were determined by ICPMS in 41 patients with dilated cardiomyopathy (DCM) and 29 presumably healthy subjects from the Katanga Copperbelt (KC), in the Democratic Republic of Congo (DRC). After adjusting for age, gender, education level, and renal function, DCM probability was almost maximal for blood concentrations above 0.75 and 150 µg/dL for arsenic and copper, respectively. Urinary concentrations above 1 for chromium, 20 for copper, 600 for zinc, 30 for selenium, 2 for cadmium, 0.2 for antimony, 0.5 for thallium, and 0.05 for uranium, all in μg/g of creatinine, were also associated with increased DCM probability. Concurrent and multiple exposures to heavy metals, well beyond permissible levels, are associated with increased probability for DCM. Study findings warrant screening for metal toxicity in case of DCM and prompt public health measures to reduce exposures in the KC, DRC.
... 20 Other studies have shown positive effects of vitamin D in HFs. 21,22 The possible mechanisms underlying the beneficial effects of vitamin D on myocardial function and HF may be related to its role in regulation of inflammation, 23,24 inhibition of myocardial cell hypertrophy and fibrosis 25 and adverse remodeling, 26 regulation of rennin-angiotensin-aldosterone system (RAAS), 27 metabolic effects of vitamin D on the cardiac muscle by affecting calcium, phosphorus, or other components of muscle contraction, 28 improvement of secondary hyperparathyroidism, which has been shown as a contributing factor to cardiac muscle dysfunction, 28,29 and direct effects of vitamin D, independent of calcium, phosphorus, or parathyroid. 30 Inflammatory cytokine [tumor necrosis factor alpha (TNF-α)] decreases and anti-inflammatory cytokine [interleukin-10 (IL-10)] increases after 9 months of treatment by vitamin D in patients with HF in comparison to the control group. ...
Background:
Low vitamin D status may contribute to the pathogenesis of heart failure (HF), but therapeutic roles of vitamin D on cardiac performance are not well known. We evaluated vitamin D effects on left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class in patients with HF for the first time.
Methods:
This study was a double-blind, randomized, placebo-controlled trial. 110 patients with HF admitted to Shahid Chamran and Khorshid Hospitals, Isfahan, Iran, randomly received 500 mg calcium daily plus either 50000 IU vitamin D3 per week (case group) or placebo (control group) for 6 months. Biochemical variables, LVEF, and NYHA functional class were assessed at baseline and after 6 months.
Results:
81 patients completed the study. Vitamin D supplementation increased mean serum 25-hydroxyvitamin D [25(OH)D] concentration in the case group by 33.9 ng/ml (P < 0.001). After 6 months of treatment, both groups showed improvement in LVEF, but the extent of improvement was significant only in the case group (5.48% versus 0.44%, P < 0.001). The NYHA functional class improved in the case group but remained constant in the control group (P < 0.001).
Conclusion:
Vitamin D3 improved LVEF and NYHA functional class in patients with HF and might serve as a new agent for the future treatment of this disease.
... The association between zinc deficiency and dilated cardiomyopathy is well documented (Oster 1993;Topuzoglu et al. 2003;Salehifar et al. 2008;Weber et al. 2009;Choi et al. 2018;Yu et al. 2018). Urinary concentrations of Zn in subjects with DCM was 4 times the reference value denoting very high excretion (Nisse et al. 2017), a commonly noted phenomenon during heart failure. ...
Blood and/or urine levels of 27 heavy metals were determined by ICPMS in 41 patients with dilated cardiomyopathy (DCM) and 29 presumably healthy subjects from the Katanga Copperbelt (KC), in the Democratic Republic of Congo (DRC). After adjusting for age, gender, education level, and renal function, DCM probability was almost maximal for blood concentrations above 0.75 and 150 µg/dl for arsenic and copper, respectively. Urinary concentrations above 1 for chromium, 20 for copper, 600 for zinc, 30 for selenium, 2 for cadmium, 0.2 for antimony, 0.5 for thallium and 0.05 for uranium, all in μg/g of creatinine, were also associated with increased DCM probability. Concurrent and multiple exposures to heavy metals, well beyond permissible levels, are associated with increased probability for DCM. Study findings warrant screening for metal toxicity in case of DCM and prompt public health measures to reduce exposures in the KC, DRC.
... In one study, vitamin D receptors were shown to affect the matrix metalloproteinase and tissue inhibitor factor. [19] Furthermore, vitamin D receptors suppress foam cell formation by reducing the levels of oxidized LDL-cholesterol. [20] Low vitamin D concentrations were shown to be related to cardiovascular diseases and mortality. ...
... 2 There is emerging evidence suggesting an important role of trace elements like chromium, zinc, cobalt, selenium, manganese and nickel in the heart and that their homeostasis imbalance may lead to an increase in the risk of cardiac remodelling in heart failure. 3 Studies have shown that these micronutrients are intricately linked to Ischemic Heart Disease (IHD). [4][5][6][7] It is well established that IHD is a global health issue and the major cause of mortality and morbidity worldwide. ...
Metals are essential cofactors that play a crucial role in heart function at the cell and tissue level. Information regarding the role of metals in the pericardial fluid and its ionome in ischemic heart disease (IHD) is limited. We aimed to determine the association of elements in pericardial fluid and serum samples of IHD patients and their correlation with systolic and diastolic function. IHD patients have been studied with systolic and diastolic dysfunction categorized on the basis of echocardiographic parameters. We measured concentrations of sixteen elements in the pericardial fluid and serum of 46 patients obtained during open heart surgery with IHD by ICP-MS. The levels of chromium and nickel in pericardial fluid were significantly higher as compared with serum samples of IHD patients (p < 0.05). The chromium, nickel and manganese levels in pericardial fluid were lower in patients with ejection fraction (EF) < 45% as compared to EF > 45% (p < 0.05). There was no significant difference in pericardial concentrations of elements in diastolic dysfunction grade 0-1 with 2 in IHD patients. We also found that decreased concentration of these elements in pericardial fluid is associated with decreased systolic function. These results suggest that pericardial fluid concentrations of these metals may reflect the extent of ischemic heart disease. These findings are hypothesis generating with regards to a role in the pathogenesis of the disorder.
