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Elevated cardiac markers in chronic kidney disease as a consequence of hyperphosphatemia-induced cardiac myocyte injury.

Wang S, Qin L, Wu T, Deng B, Sun Y, Hu D, Mohan C, Zhou XJ, Peng A - Med. Sci. Monit. (2014)

Bottom Line: Then, the effect of reducing phosphorus levels on CMs by taking phosphate binder for 3 months was prospectively observed in 64 hemodialysis patients.Finally, human cardiomyocytes were exposed to different concentrations of inorganic phosphorus to examine its underlying mechanism. 1) Serum phosphorus and CMs gradually increased as the glomerular filtration rate declined in CKD patients (p<0.01). 2) Elevation of CMs was much greater and cardiac structure and function were worse in CKD patients who had higher serum phosphorus concentrations (p<0.05). 3) Serum phosphorus level positively correlated with cTnT, MYO, and BNP in CKD patients (p<0.001). 4) In hemodialysis patients, the reduction of cTnT, MYO, and CK-MB was synchronous with the pharmacologically-induced decline of serum phosphorus level.Hyperphosphatemia may induce myocardial damage in CKD patients, possibly through triggering apoptosis of human cardiomyocytes, and this could account for the elevated cardiac markers in CKD patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology and Rheumatology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China (mainland).

ABSTRACT

Background: Elevated cardiac markers (CMs) and hyperphosphatemia are commonly encountered in patients with chronic kidney diseases (CKD), but the causal relationship between them has not been established.

Material and methods: We enrolled 151 patients with different kidney functions in a cross-sectional study to explore the relationship of serum phosphorus with CMs, including cardiac troponin T (cTnT), myoglobin (MYO), creatine kinase-MB (CK-MB), and brain natriuretic peptide (BNP). Then, the effect of reducing phosphorus levels on CMs by taking phosphate binder for 3 months was prospectively observed in 64 hemodialysis patients. Finally, human cardiomyocytes were exposed to different concentrations of inorganic phosphorus to examine its underlying mechanism.

Results: 1) Serum phosphorus and CMs gradually increased as the glomerular filtration rate declined in CKD patients (p<0.01). 2) Elevation of CMs was much greater and cardiac structure and function were worse in CKD patients who had higher serum phosphorus concentrations (p<0.05). 3) Serum phosphorus level positively correlated with cTnT, MYO, and BNP in CKD patients (p<0.001). 4) In hemodialysis patients, the reduction of cTnT, MYO, and CK-MB was synchronous with the pharmacologically-induced decline of serum phosphorus level. However, levels of serum Fibroblast growth factor 23 (FGF23) had no statistical decrease. 5) Simulated hyperphosphatemia inhibited proliferation of human cardiomyocytes in a time- and concentration-dependent manner.

Conclusions: Hyperphosphatemia may induce myocardial damage in CKD patients, possibly through triggering apoptosis of human cardiomyocytes, and this could account for the elevated cardiac markers in CKD patients.

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Related in: MedlinePlus

Effect of phosphate on proliferation and apoptosis of human cardiac myocytes (HCMs). After incubation for 24 h, compared to the HCMs cultured in 1mmol/L inorganic phosphorus (A), apoptotic cells increased when cultured in medium with 3 mmol/L phosphorus (B). This effect was inhibited by adding 1 mmol/L of PFA, a specific inhibitor of phosphate transport (C). MTT assay (D) showed phosphorus overload in moderately-inhibited HCMs proliferation in a time- and concentration-dependant manner (* p<0.05, ** p<0.01). Compared to HCMs cultured in 1 mmol/L of phosphorus, apoptotic cells and necrotic cells of HCMs in medium with 3 mmol/L of inorganic phosphate increased after incubation for 12 h (E), 24 h (F), and 36 h (G). When 1 mmol/L of PFA was added, apoptotic and necrotic cells decreased after 24 h of incubation (F). Western blot analysis (H) showed that expression of cleaved Caspase-3 increased in cells cultured in medium with 3 mmol/L of phosphate compared to medium with 1 mmol/L of phosphate. However, this up-regulating effect was inhibited when 1 mmol/L of PFA was added. (I–K) The expression of uncleaved Caspase-3 protein exhibited a reciprocal pattern to that of cleaved Caspase-3, but the expression of apoptosis-inducing factor (AIF) proteins exhibited no significant change.
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f2-medscimonit-20-2043: Effect of phosphate on proliferation and apoptosis of human cardiac myocytes (HCMs). After incubation for 24 h, compared to the HCMs cultured in 1mmol/L inorganic phosphorus (A), apoptotic cells increased when cultured in medium with 3 mmol/L phosphorus (B). This effect was inhibited by adding 1 mmol/L of PFA, a specific inhibitor of phosphate transport (C). MTT assay (D) showed phosphorus overload in moderately-inhibited HCMs proliferation in a time- and concentration-dependant manner (* p<0.05, ** p<0.01). Compared to HCMs cultured in 1 mmol/L of phosphorus, apoptotic cells and necrotic cells of HCMs in medium with 3 mmol/L of inorganic phosphate increased after incubation for 12 h (E), 24 h (F), and 36 h (G). When 1 mmol/L of PFA was added, apoptotic and necrotic cells decreased after 24 h of incubation (F). Western blot analysis (H) showed that expression of cleaved Caspase-3 increased in cells cultured in medium with 3 mmol/L of phosphate compared to medium with 1 mmol/L of phosphate. However, this up-regulating effect was inhibited when 1 mmol/L of PFA was added. (I–K) The expression of uncleaved Caspase-3 protein exhibited a reciprocal pattern to that of cleaved Caspase-3, but the expression of apoptosis-inducing factor (AIF) proteins exhibited no significant change.

Mentions: In the in vitro study, a 3-mM concentration of inorganic phosphate induced apoptosis and necrosis of human cardiac myocytes (HCMs). However, the majority death type of HCMs was recognized as apoptosis, based on the analysis of cell numbers (Figure 2) and morphology of dead cells (features of necrosis like cell swelling and plasma membrane damage were observed, data not shown). Phosphorus added to the medium inhibited HCMs proliferation in a time- and concentration-dependant manner. Compared with HCMs cultured in medium with 1mmol/L phosphorus, viable cells decreased, while necrotic and apoptotic cells increased when HCMs were cultured in medium with 3 mmol/L of phosphorus, at all time periods (Figure 2).


Elevated cardiac markers in chronic kidney disease as a consequence of hyperphosphatemia-induced cardiac myocyte injury.

Wang S, Qin L, Wu T, Deng B, Sun Y, Hu D, Mohan C, Zhou XJ, Peng A - Med. Sci. Monit. (2014)

Effect of phosphate on proliferation and apoptosis of human cardiac myocytes (HCMs). After incubation for 24 h, compared to the HCMs cultured in 1mmol/L inorganic phosphorus (A), apoptotic cells increased when cultured in medium with 3 mmol/L phosphorus (B). This effect was inhibited by adding 1 mmol/L of PFA, a specific inhibitor of phosphate transport (C). MTT assay (D) showed phosphorus overload in moderately-inhibited HCMs proliferation in a time- and concentration-dependant manner (* p<0.05, ** p<0.01). Compared to HCMs cultured in 1 mmol/L of phosphorus, apoptotic cells and necrotic cells of HCMs in medium with 3 mmol/L of inorganic phosphate increased after incubation for 12 h (E), 24 h (F), and 36 h (G). When 1 mmol/L of PFA was added, apoptotic and necrotic cells decreased after 24 h of incubation (F). Western blot analysis (H) showed that expression of cleaved Caspase-3 increased in cells cultured in medium with 3 mmol/L of phosphate compared to medium with 1 mmol/L of phosphate. However, this up-regulating effect was inhibited when 1 mmol/L of PFA was added. (I–K) The expression of uncleaved Caspase-3 protein exhibited a reciprocal pattern to that of cleaved Caspase-3, but the expression of apoptosis-inducing factor (AIF) proteins exhibited no significant change.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4214699&req=5

f2-medscimonit-20-2043: Effect of phosphate on proliferation and apoptosis of human cardiac myocytes (HCMs). After incubation for 24 h, compared to the HCMs cultured in 1mmol/L inorganic phosphorus (A), apoptotic cells increased when cultured in medium with 3 mmol/L phosphorus (B). This effect was inhibited by adding 1 mmol/L of PFA, a specific inhibitor of phosphate transport (C). MTT assay (D) showed phosphorus overload in moderately-inhibited HCMs proliferation in a time- and concentration-dependant manner (* p<0.05, ** p<0.01). Compared to HCMs cultured in 1 mmol/L of phosphorus, apoptotic cells and necrotic cells of HCMs in medium with 3 mmol/L of inorganic phosphate increased after incubation for 12 h (E), 24 h (F), and 36 h (G). When 1 mmol/L of PFA was added, apoptotic and necrotic cells decreased after 24 h of incubation (F). Western blot analysis (H) showed that expression of cleaved Caspase-3 increased in cells cultured in medium with 3 mmol/L of phosphate compared to medium with 1 mmol/L of phosphate. However, this up-regulating effect was inhibited when 1 mmol/L of PFA was added. (I–K) The expression of uncleaved Caspase-3 protein exhibited a reciprocal pattern to that of cleaved Caspase-3, but the expression of apoptosis-inducing factor (AIF) proteins exhibited no significant change.
Mentions: In the in vitro study, a 3-mM concentration of inorganic phosphate induced apoptosis and necrosis of human cardiac myocytes (HCMs). However, the majority death type of HCMs was recognized as apoptosis, based on the analysis of cell numbers (Figure 2) and morphology of dead cells (features of necrosis like cell swelling and plasma membrane damage were observed, data not shown). Phosphorus added to the medium inhibited HCMs proliferation in a time- and concentration-dependant manner. Compared with HCMs cultured in medium with 1mmol/L phosphorus, viable cells decreased, while necrotic and apoptotic cells increased when HCMs were cultured in medium with 3 mmol/L of phosphorus, at all time periods (Figure 2).

Bottom Line: Then, the effect of reducing phosphorus levels on CMs by taking phosphate binder for 3 months was prospectively observed in 64 hemodialysis patients.Finally, human cardiomyocytes were exposed to different concentrations of inorganic phosphorus to examine its underlying mechanism. 1) Serum phosphorus and CMs gradually increased as the glomerular filtration rate declined in CKD patients (p<0.01). 2) Elevation of CMs was much greater and cardiac structure and function were worse in CKD patients who had higher serum phosphorus concentrations (p<0.05). 3) Serum phosphorus level positively correlated with cTnT, MYO, and BNP in CKD patients (p<0.001). 4) In hemodialysis patients, the reduction of cTnT, MYO, and CK-MB was synchronous with the pharmacologically-induced decline of serum phosphorus level.Hyperphosphatemia may induce myocardial damage in CKD patients, possibly through triggering apoptosis of human cardiomyocytes, and this could account for the elevated cardiac markers in CKD patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology and Rheumatology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China (mainland).

ABSTRACT

Background: Elevated cardiac markers (CMs) and hyperphosphatemia are commonly encountered in patients with chronic kidney diseases (CKD), but the causal relationship between them has not been established.

Material and methods: We enrolled 151 patients with different kidney functions in a cross-sectional study to explore the relationship of serum phosphorus with CMs, including cardiac troponin T (cTnT), myoglobin (MYO), creatine kinase-MB (CK-MB), and brain natriuretic peptide (BNP). Then, the effect of reducing phosphorus levels on CMs by taking phosphate binder for 3 months was prospectively observed in 64 hemodialysis patients. Finally, human cardiomyocytes were exposed to different concentrations of inorganic phosphorus to examine its underlying mechanism.

Results: 1) Serum phosphorus and CMs gradually increased as the glomerular filtration rate declined in CKD patients (p<0.01). 2) Elevation of CMs was much greater and cardiac structure and function were worse in CKD patients who had higher serum phosphorus concentrations (p<0.05). 3) Serum phosphorus level positively correlated with cTnT, MYO, and BNP in CKD patients (p<0.001). 4) In hemodialysis patients, the reduction of cTnT, MYO, and CK-MB was synchronous with the pharmacologically-induced decline of serum phosphorus level. However, levels of serum Fibroblast growth factor 23 (FGF23) had no statistical decrease. 5) Simulated hyperphosphatemia inhibited proliferation of human cardiomyocytes in a time- and concentration-dependent manner.

Conclusions: Hyperphosphatemia may induce myocardial damage in CKD patients, possibly through triggering apoptosis of human cardiomyocytes, and this could account for the elevated cardiac markers in CKD patients.

Show MeSH
Related in: MedlinePlus