Abstract 12877: Magnesium Deficiency Causes Reversible Metabolic Diastolic and Systolic Cardiomyopathies

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Man Liu ◽  
Hong LIU ◽  
Feng Feng ◽  
An Xie ◽  
Cody R Hou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Magnesium Deficiency ◽  
Diastolic Heart Failure ◽  
Cellular Level ◽  
Normal Diet ◽  
Ca Channel ◽  
Mg Deficiency ◽  
Mitochondrial Membrane Depolarization

Introduction: Low circulating magnesium (Mg) level is associated with increased cardiovascular mortality, and conversely, dietary Mg intake is associated with a decreased risk of developing heart failure. Hypothesis: We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks (low→nl-Mg group). Results: Mg deficiency increased mortality, especially in female mice. After 6 weeks of low-Mg diet, surviving mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K, and Na. Low-Mg mice exhibited a decreased cardiac ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg) and impaired relaxation (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg) in echocardiography. At the cellular level, ATP, Ca transient amplitude, sarcoplasmic reticulum (SR) Ca load, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts and cardiomyocytes. These changes were accompanied by evidence of mitochondrial dysfunction with significantly increased mitochondrial ROS production and mitochondrial membrane depolarization. Mg repletion normalized electrolytes, contraction, relaxation, and cellular changes. The SR Ca pump (SERCA) was decreased, the SR Ca channel RyR2 oxidized, and cardiac myosin binding protein C S-glutathionylated in low-Mg mouse hearts. These changes were normalized with Mg repletion. In vivo , mitoTEMPO treatment during low Mg diet improved the cardiac relaxation and increased cellular ATP levels without improving contraction. Conclusions: Mg deficiency caused a reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake could reverse these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms and mortality. In deficiency states, Mg supplementation may represent a novel treatment for systolic and diastolic heart failure.

Abstract 218: Magnesium Deficiency Causes Reversible Diastolic and Systolic Cardiomyopathies by Impairing Mitochondrial Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
An Xie ◽  
Xiaoxu Zhou ◽  
Feng Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Magnesium Deficiency ◽  
Systolic Heart Failure ◽  
Cellular Level ◽  
Normal Diet ◽  
Mg Deficiency ◽  
Developing Heart ◽  
Patients With Diabetes ◽  
Relationship Of

Introduction: Hypomagnesemia is common in patients with diabetes, hypertension, and heart failure. A low circulating Mg level is associated with increased cardiovascular mortality, and conversely, dietary magnesium (Mg) intake is associated with a decreased risk of developing heart failure. In this study, we investigated whether Mg deficiency alone contributed to cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal Mg diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks. Results: Mg deficiency increased mortality. The survival rate after 6-week low-Mg diet was 0 for female and 64.6% for male. Surviving male mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K and Na. Mg deficiency was associated with a decreased ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg), diastolic dysfunction (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg), and prolonged QTc intervals (55.1±0.8 vs. 46.0±1.2 ms of nl-Mg). At the cellular level, ATP, Ca transient amplitude, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts. These changes were accompanied by significantly increased mitochondrial ROS production. Reintroduction of Mg normalized electrolytes, EF% (52.1±1.4%), E/e’ (15.3±0.7), QTc (49.4±1.7 ms) and cellular changes. SERCA2 was decreased, and oxidation of RyR2 and cardiac myosin binding protein C were increased in low-Mg hearts, all of which were reversed by Mg repletion. In vivo mitoTEMPO treatment on low-Mg mice (1 mg/kg/day IP injection for 2 weeks) improved the diastolic function (E/e’=16.7±2.0) and increased cellular ATP levels. Conclusion: Mg deficiency causes reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake reverses these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms. In deficiency states, Mg supplementation may represent a novel treatment for both diastolic and systolic heart failure.

scholarly journals Magnesium Deficiency Causes a Reversible, Metabolic, Diastolic Cardiomyopathy

2021 ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Feng Feng ◽  
An Xie ◽  
Gyeoung‐Jin Kang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Magnesium Deficiency ◽  
Diastolic Heart Failure ◽  
Oxidative Modification ◽  
Mouse Serum ◽  
Mg Deficiency ◽  
Developing Heart ◽  
Cardiac Relaxation

Background Dietary Mg intake is associated with a decreased risk of developing heart failure, whereas low circulating Mg level is associated with increased cardiovascular mortality. We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods and Results C57BL/6J mice were fed with a low Mg (low‐Mg, 15–30 mg/kg Mg) or a normal Mg (nl‐Mg, 600 mg/kg Mg) diet for 6 weeks. To test reversibility, half of the low‐Mg mice were fed then with nl‐Mg diet for another 6 weeks. Low‐Mg diet significantly decreased mouse serum Mg (0.38±0.03 versus 1.14±0.03 mmol/L for nl‐Mg; P <0.0001) with a reciprocal increase in serum Ca, K, and Na. Low‐Mg mice exhibited impaired cardiac relaxation (ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e, 21.1±1.1 versus 15.4±0.4 for nl‐Mg; P =0.011). Cellular ATP was decreased significantly in low‐Mg hearts. The changes were accompanied by mitochondrial dysfunction with mitochondrial reactive oxygen species overproduction and membrane depolarization. cMyBPC (cardiac myosin‐binding protein C) was S ‐glutathionylated in low‐Mg mouse hearts. All these changes were normalized with Mg repletion. In vivo (2‐(2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino)‐2‐oxoethyl)triphenylphosphonium chloride treatment during low‐Mg diet improved cardiac relaxation, increased ATP levels, and reduced S ‐glutathionylated cMyBPC. Conclusions Mg deficiency caused a reversible diastolic cardiomyopathy associated with mitochondrial dysfunction and oxidative modification of cMyBPC. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure.

scholarly journals On the origin of the increased tissue iron content in graded magnesium deficiency states in the rat

1997 ◽  
Vol 77 (3) ◽  
pp. 475-490 ◽  
Author(s):  
Klaus Schumann ◽  
Annette Lebeau ◽  
Ursula Gresser ◽  
Theodor Gunther ◽  
Jürgen Vormann
Keyword(s):  
Haemolytic Anaemia ◽  
Rapid Growth ◽  
Magnesium Deficiency ◽  
Erythropoietic Activity ◽  
Mg Deficiency ◽  
Adequate Diet ◽  
Fe Content ◽  
High Degree

To investigate the mechanism of tissue Fe accumulation in graded Mg deficiency rats were fed on diets of different Mg contents (70, 110, 208, 330, and 850 mg Mg/kg) for 10, 20, and 30 d during rapid growth. There was no significant impact of Mg deficiency or high luminal Mg concentrations on intestinal59Fe transferin vitroorin vivo. Plasma Mg concentrations and body weight started to decrease after 10 d. Significant haemolytic anaemia was observed after 20 d with siderosis in liver and spleen developing in parallel. Anaemia showed no features of Fe deficiency or infiammation. Comparison between the 70 mg Mg/kg group and animals that received the same quantity of a Mg-adequate diet (850 mg Mg/kg) permitted estimation of quantities of Fe liberated by haemolysis and the increased Fe content in liver and spleen. Both variables showed a high degree of correlation, indicating that the excess of liberated haemoglobin Fe was stored in the tissue. The erythropoietic activity was high during rapid growth, i.e. at days 10 and 20 and decreased significantly after 30 d in all except the most Mg-deficient groups. However, haemolytic anaemia developed because even the high erythropoietic activity in the 70 and 110 mg Mg/kg groups was not sutlicient to recycle all haemoglobin Fe liberated by haemolysis. After 30 d of Mg-deficient feeding the erythrocyte Mg content had decreased to 40% of control values. According to the literature Mg-deficient erythrocytes have a decreased survival time which is likely to be the cause of the observed haemolysis.

Magnesium Homeostasis and Clinical Disorders of Magnesium Deficiency

1994 ◽  
Vol 28 (2) ◽  
pp. 220-226 ◽  
Author(s):  
Robert Whang ◽  
Edward M. Hampton ◽  
David D. Whang
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Congestive Heart Failure ◽  
Critically Ill ◽  
Clinical Studies ◽  
Magnesium Deficiency ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Digitalis Toxicity ◽  
Mg Deficiency

OBJECTIVE: To survey the causes of clinical hypomagnesemia and Mg deficiency. The relationship of hypomagnesemia to digitalis toxicity, congestive heart failure, arrhythmias, and acute myocardial infarction is discussed, as is the clinical interrelationship of Mg and K concentrations, the principal intracellular cations. DATA SOURCES: A MEDLINE search and retrieval was used to identify relevant references. STUDY SELECTION: Clinical reports, as well as studies, were selected for this review. DATA EXTRACTION: There were very few placebo-controlled clinical studies. Clinical observations were related primarily to compilation of series in which Mg was administered and clinical results reported. In addition, conclusions derived from review articles on the subject of clinical Mg depletion were used. DATA SYNTHESIS: Clinical diagnosis of Mg deficiency is ascertained most expeditiously by estimating serum Mg concentrations. Although available on order by physicians, the lack of routine serum Mg analysis as part of the “electrolyte panel” impedes the diagnosis of clinical Mg deficiency. Renal loss of Mg resulting from the widespread use of loop diuretics is responsible for significant numbers of patients with Mg deficiency and hypomagnesemia. Life threatening cardiac arrhythmias and seizures represent the most serious manifestations of clinical hypomagnesemia and Mg depletion. In the most critically ill patients, treatment with intravenous Mg is recommended. Oral repletion of Mg is reserved for the less critically ill hospitalized patients and ambulatory patients. Close attention must be paid to optimizing K replenishment in hypokalemic patients by concurrent treatment of any accompanying hypomagnesemia to avoid the problem of refractory K repletion. CONCLUSIONS: Hypomagnesemia is one of the most frequent serum electrolyte abnormalities in current clinical practice. Routine inclusion of serum Mg analysis in the electrolyte panel will enhance the clinical recognition and treatment of hypomagnesemic Mg-depleted patients. Failure to respond to treatment of recurrent ventricular tachycardia/fibrillation to usual antiarrhythmic therapy in patients with acute myocardial infarction, idiopathic dilated cardiomyopathy, and congestive heart failure should alert the clinician to consider administering intravenous Mg. Repair of coexisting hypomagnesemia in hypokalemic patients is essentialto avoid the problem of refractory K repletion caused by coexisting Mg depletion. More controlled clinical studies of Mg deficiency are necessary to ascertain the cost-effectiveness of Mg replacement therapy.

Abstract 17473: GRK2 in the Mitochondria: Uncovering Novel Mechanisms in Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kimberly M Ferrero ◽  
Gizem Kayki Mutlu ◽  
Jessica M Pfleger ◽  
Douglas G Tilley ◽  
Walter J Koch
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Ventricular Myocytes ◽  
Atp Synthesis ◽  
Neonatal Rat ◽  
Negative Effects ◽  
Protein Kinase C Inhibitor ◽  
Neonatal Rat Ventricular Myocytes

Introduction: During heart failure, levels and activity of G protein-coupled receptor kinase 2 (GRK2) increase. GRK2 is canonically studied in the phosphorylation of GPCRs and β-adrenergic desensitization. Noncanonical activities of GRK2 are being uncovered, however. Our lab has recently discovered that in cardiac myocytes, GRK2 translocates to the mitochondria ( mtGRK2 ) following injury and is associated with negative effects on metabolism and cell survival. Hypothesis: GRK2 plays a role in regulating mitochondrial function following cardiac stress and contributes to HF pathogenesis in a novel manner, by interacting with a novel group of mitochondrial proteins involved in pro-death signaling, bioenergetics and substrate utilization. Methods: Mitochondrial translocation of GRK2 was validated with either protein kinase C inhibitor (chelerythine) administration or hypoxia/reoxygenation stress in primary neonatal rat ventricular myocytes or a cardiac-like cell line. Immunoprecipitation of the GRK2 interactome basally and under stress conditions was conducted endogenously in vitro, in vivo , and with purified recombinant GRK2 peptides. Proteins were separated via SDS-PAGE and potential binding partners were identified by mass spectroscopy (LCMS) and proteomics analysis conducted with Ingenuity Pathway (IPA; Qiagen) software to determine which partners in the GRK2 interactome were potentially involved in mitochondrial dysfunction. Results: Subunits of Complexes I, II, IV and V of the electron transport chain were identified as potential mtGRK2 interacting partners. Several mtGRK2-ETC interactions were increased following oxidative stress-induced translocation of GRK2. Finally, mtGRK2 appears to phosphorylate some of the interactome partners identified in mitochondrial dysfunction. Conclusions: The phosphorylation of subunits of the ATP synthesis machinery by mtGRK2, or other mechanisms of interaction between these proteins, may be regulating some of the phenotypic effects of HF previously observed by our lab, such as increased ROS production and reduced fatty acid metabolism. Further research is essential to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death in failing hearts.

Abstract P310: Mitochondrial Electron Transport Chain Dysfunction Is Associated With Mg Deficiency Induced Diastolic Dysfunction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Richard T Clements ◽  
Feng Feng ◽  
Jin O-Uchi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Electron Transport ◽  
Diastolic Dysfunction ◽  
Mitochondrial Function ◽  
Complex I ◽  
Electron Transport Chain ◽  
Diastolic Heart Failure ◽  
Mg Deficiency ◽  
Transport Chain ◽  
Mg Content

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, although there is no specific treatment for HFpEF yet because of poor understanding of the underlying pathophysiology. Our previous studies show that hypomagnesemia contributes to diastolic dysfunction and HFpEF by regulation of mitochondrial function and that Mg supplementation improves diastolic function. In this study, we investigated how mitochondria were affected by Mg deficiency. Methods: C57BL/6J mice were fed with a low-Mg diet (HypoMg mice, 15-30 mg/kg Mg) or a normal Mg diet (control mice, 600 mg/kg Mg) for 6 weeks. Mg repletion was achieved by feeding HypoMg mice with normal diet for another 6 weeks. Results: HypoMg mice showed significantly decreased serum Mg (0.38±0.03 mM vs. 1.14±0.03 mM of control, P<0.0001), diastolic dysfunction (E/e’=21.1±1.1 vs. 15.4±0.4 of control, P=0.011), increased mitochondrial ROS (1.9±0.2-fold of control, P<0.0001), decreased total mitochondrial Mg content (3.6±1.8 vs. 18.3±4.7 μM total Mg/mg mitochondrial protein of control, P=0.019), decreased ATP production in hearts (1.2±0.2 vs. 2.7±0.2 μmol/g heart tissue of control, P=0.0002), decreased complex I activity (ΔOCR NADH-rotenone =0.27±0.10 vs. 1.02±0.04 of control, P=0.0004 measured with Seahorse), and decreased complex I protein levels (50.2% reduction compared with control mice, P=0.009). Mg repletion reversed all these changes. Conclusion: HypoMg-induced diastolic dysfunction likely results from HypoMg-induced electron transport chain dysfunction resulting from a decrease in mitochondrial Mg content. Mg repletion reverses these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure by improving mitochondrial function.

scholarly journals Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

Diabetologia ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 2218-2234
Author(s):  
Christian Stern ◽  
Barbara Schreier ◽  
Alexander Nolze ◽  
Sindy Rabe ◽  
Sigrid Mildenberger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Smooth Muscle ◽  
Mitochondrial Dysfunction ◽  
Renal Damage ◽  
Egf Receptor ◽  
Vascular Dysfunction ◽  
Cellular Level

Abstract Aims/hypothesis Obesity causes type 2 diabetes leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesity-induced renovascular dysfunction, as well as EGFR–hyperglycaemia crosstalk. Methods The role of VSM-EGFR during high-fat diet (HFD)-induced type 2 diabetes was investigated in a mouse model with inducible, VSM-specific EGFR-knockout (KO). Various structural and functional variables as well as transcriptome changes, in vivo and ex vivo, were assessed. The impact of hyperglycaemia on EGFR-induced signalling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results We show that VSM-EGFR mediates obesity/type 2 diabetes-induced vascular dysfunction, remodelling and transcriptome dysregulation preceding renal damage and identify an EGFR–glucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR deletion protects the animals from HFD-induced endothelial dysfunction, creatininaemia and albuminuria. Furthermore, we show that HFD leads to marked changes of the aortic transcriptome in wild-type but not in KO animals, indicative of EGFR-dependent SRF activation, matrix dysregulation and mitochondrial dysfunction, the latter confirmed at the cellular level. Studies at the cellular level revealed that high glucose potentiated EGFR/EGF receptor 2 (ErbB2)-induced stimulation of SRF activity, enhancing the graded signalling responses to EGF, via the EGFR/ErbB2–ROCK–actin–MRTF pathway and promoted mitochondrial dysfunction. Conclusions/interpretation VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations. We propose that a potentiated EGFR/ErbB2–ROCK–MRTF–SRF signalling axis and mitochondrial dysfunction underlie the role of EGFR. This advanced working hypothesis will be investigated in mechanistic depth in future studies. VSM-EGFR may be a therapeutic target in cases of type 2 diabetes-induced renovascular disease. Data availability The datasets generated during and/or analysed during the current study are available in: (1) share_it, the data repository of the academic libraries of Saxony-Anhalt (10.25673/32049.2); and (2) in the gene expression omnibus database with the study identity GSE144838 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144838).

scholarly journals Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure

2012 ◽  
Vol 303 (5) ◽  
pp. H587-H596 ◽  
Author(s):  
Anthony G. Garcia ◽  
Richard M. Wilson ◽  
Joline Heo ◽  
Namita R. Murthy ◽  
Simoni Baid ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Salt Water ◽  
Diastolic Heart Failure ◽  
Velocity Ratio ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Left Ventricular

Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) mice underwent either saline ( n = 12) or aldosterone ( n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNγ (250 U/ml) and/or aldosterone (1 μM). Hypertension was less marked in IFNγKO-aldosterone mice than in WT-aldosterone mice (127 ± 5 vs. 136 ± 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 ± 0.1 vs. 4.3 ± 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 ± 0.1 vs. 2.8 ± 0.1). LV ejection fraction was no different between IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.

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