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AGE-RAGE Axis in the Aging and Diabetic Heart
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Karen M. O’Shea, Ann Marie Schmidt, Ravichandran Ramasamy
Impaired calcium homeostasis is a hallmark of diabetes and heart failure. The tight regulation of calcium transients during systole and diastole is directly responsible for regulating contraction and relaxation of the contractile apparatus in cardiomyocytes. For a more detailed review of the role of calcium in the heart and the progression to heart failure, the reader is referred to (Gorski et al. 2015). Depolarization of the sarcolemma triggers the L-type caclium channels to allow entry of a small amount of extracellular calicum into the cytosol. This calcium then binds to RyR on the sarcoplasmic reticulum, prompting the release of stored calcium from the sarcoplasmic reticulum into the cytosol, a process termed calcium-induced calcium release. This results in an approximate 10-fold increase in cytosolic calcium, which can then bind to troponin and induce a conformational change that allows for contraction of the contractile apparatus. In order for relaxation to occur, the calcium must be cleared from the cytosol. This primarily occurs through the activity of the SERCA, which pumps calcium back into the sarcoplasmic reticulum at the cost of ATP. Additionally, the sodium-calcium exchanger (NCX) at the sarcolemma extrudes calcium from the cytosol in exchange for sodium entry into the cytosol.
Mitochondrial Transplantation in Myocardial Ischemia and Reperfusion Injury
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
David Blitzer, Borami Shin, Alvise Guariento, Pedro J. del Nido, James D. McCully
Despite the auto-protective mechanisms, prolonged ischemia is inevitably succeeded by irreversible myocardial injury. Numerous studies have been performed to elucidate the intracellular pathways of this irreversible ischemic injury and have identified a central role for mitochondrial injury in the intracellular cascade leading to myocyte death. With the depletion of ATP, multiple changes occur in the mitochondria at the biochemical and ultrastructural levels. These include cellular acidosis and the accumulation of Ca2+ within the cytoplasm, the mitochondria, and the nucleus. Oxygen depletion within the myocardium signals for a change from fatty acid oxidation to anaerobic glycolysis with a resulting accumulation of lactate and intracellular acidosis, which is readily measured with a pH probe or by tissue PCO2 and 21P NMR spectroscopy [124,125]. With the accumulation of intracellular hydrogen (H+) the sodium-hydrogen exchanger (NHE) opens, with resulting increases in extracellular H+ and intracellular Na+ [126]. The sodium-calcium exchanger (NCX) on the plasma membrane then acts, in reverse, to reduce the intracellular Na+ load. This, in turn causes an increase in cytosolic Ca2+ which is augmented by opening of the L-type Ca2+ channels as a result of the depolarization at the plasma membrane. Furthermore, with the diminished availability of ATP sarcoplasmic reticulum by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) stops taking up excess Ca2+ [127]. With the accumulation of cytoplasmic Ca2+ comes activation of Ca2+-dependent phospholipases and proteases leading to injury of the cellular membrane and continued accumulation of intracellular Ca2+.
The Pathophysiology of Heart Failure with Preserved Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Vishal N. Rao, Kishan S. Parikh
Prolonged myocardial relaxation, along with passive stiffness, is believed to serve as one physiological component of HFpEF (Figure 4.2).13 Delayed or impaired diastolic relaxation results in elevations in ventricular end-diastolic pressures with incremental changes in cardiac filling.13,29–32 The ventricular relaxation delay becomes physiologically apparent under certain vascular loading states30 or at faster heart rates with reduced total diastolic filling time.33 Various mechanisms that prolong myocardial relaxation have been proposed.34 In normal ventricles, calcium removal from the cardiomyocyte cytosol is integral to active relaxation via phospholamban (PLB)-modulated uptake of calcium into the sarcoplasmic reticulum by a calcium-ATPase, calcium extrusion via a sodium-calcium exchanger, mitochondrial calcium uniport, and sarcolemmal calcium-ATPase.34,35 In HFpEF, cytosolic calcium is incompletely removed and the sarcoplasmic reticulum stores of calcium for the next systolic cycle are reduced due to calcium-ATPase inactivity (SERCA2a), likely due to reduced protein expression and by reduced phosphorylation of its inhibitory modulating protein. Active relaxation is further reduced in HFpEF due to downregulation of beta-adrenergic receptor expression36 and depressed responsiveness,37 contributing to signaling irregularities and downstream myocardial changes. Furthermore, the myofilament titin and other elastic elements and their restoring forces facilitate sarcomere movement toward resting length in diastole as well as in the regulation of calcium activation/deactivation during the cardiac cycle, so that reduced levels of titin may contribute to the diastolic dysfunction and reduced myocardial efficiency in HFpEF.38
Computational modeling of stretch induced calcium signaling at the apical membrane domain in umbrella cells
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
Amritanshu Gupta, Rohit Manchanda
Sub-cellularly, morphological studies of UCs have shown clusters of mitochondria and an abundant presence of discoidal fusiform vesicles (DFVs) in the sub-apical-plasma membrane domain (Jost et al. 1989). In stretched UCs, several DFVs and mitochondria align parallel to the apical plasma membrane packing the space occupied by the sub-apical cytoplasm (Hudoklin et al. 2012). Keeping in mind this structural arrangement in UCs, we envisage that this structural adaptation, i.e., an abundant presence of DFVs and clusters of sub-apical mitochondria, results in a tightly packed cytosolic sub-compartment under the apical membrane, which we term as the “sub-plasma membrane space” or, for brevity, SPMS. With reference to mitochondria, in various cell types, particularly secretory epithelial cells, mitochondria are well known for their role in cycling/buffering Ca2+ (Rizzuto et al. 1999; Voronina et al. 2014). This is made possible via a specialised Ca2+ handling toolkit on the mitochondrial membrane, which includes the low Ca2+ affinity Uniporter (MCU) responsible for the uptake of Ca2+ and the sodium-calcium exchanger (NCX) which pumps out Ca2+ back into the cytosol (Finkel et al. 2015).
Emerging sodium-glucose cotransporter-2 inhibitor therapies for managing heart failure in patients with chronic kidney disease
Published in Expert Opinion on Pharmacotherapy, 2023
Jeffrey Shi Kai Chan, Francesco Perone, Yasmin Bayatpoor, Gary Tse, Amer Harky
Beyond the intended renal effects, SGLT2 inhibitors also have numerous direct and indirect cardiac effects, which are clinically important [43], with studies having demonstrated that SGLT2 inhibitors lead to significant cardiac remodeling [44,45]. Instead of SGLT2, cardiomyocytes express SGLT1, which is upregulated together with sodium-hydrogen exchanger 1 in the presence of both type 2 DM and HF [46,47]. This increases cytosolic sodium levels which, in turn, increases cytosolic calcium levels by promoting calcium influx via membrane-bound sodium – calcium exchanger transporters, as well as promoting calcium shift from mitochondria into the cytosol via sodium – calcium exchanger transporters. The elevated cytosolic calcium levels reduce calcium transients and sarcoplasmic reticulum calcium reserve, resulting in diminished contractile function [47,48]. SGLT2 inhibitors inhibit both sodium-hydrogen exchanger 1 and SGLT1 to reverse calcium overload [48–52], an effect that is independent of diabetic status [53]. SGLT2 inhibitors also influence atrial mitochondrial function and metabolism, ameliorating structural and electrical remodeling of the atria in type 2 DM [44]. Adverse atrial remodeling has been observed in patients with HF to be predictive of poor outcomes [44], and the ability of SGLT2 inhibitors to ameliorate atrial remodeling may explain the agents’ clinical effects on atrial fibrillation and other arrhythmias [54–56].
A single-center experience of parathyroidectomy in 1500 cases for secondary hyperparathyroidism: a retrospective study
Published in Renal Failure, 2022
Shasha Zhao, Wei Gan, Wenjia Xie, Jinlong Cao, Liang Zhang, Ping Wen, Junwei Yang, Mingxia Xiong
Another issue that needs to be emphasized is postsurgical hyperkalemia, which has been reported in previous studies [20,21]. To date, several underlying mechanisms of postoperative hyperkalemia have been proposed. First, hyperkalemia is common among uremic patients, and tissue destruction caused by surgery further increases the risk. Another possible mechanism is as follows [20–24]: a sharp decline in serum iPTH levels leads to calcium influx into bone. Then, sodium ion influx into skeletal muscle cells increases through the membrane barrier action of the sodium–calcium exchanger. Increased sodium ion levels in skeletal muscle cells can reduce potassium ion influx by influencing the activation of the Na/K ATPase pump, which results in increased levels of extracellular potassium. To date, preoperative serum potassium, serum alkaline phosphatase, and dosage of calcium supplementation have been identified as factors influencing serum potassium levels after surgery [20,21,25]. To prevent cardiovascular events caused by hyperkalemia, a low potassium diet, increasing the dialysis frequency and routine electrolyte monitoring may play a certain role.