Ischemic cardiomyopathy (ICM) is a special type of coronary heart disease or an advanced stage of the disease, which is related to the pathological mechanism of primary dilated cardiomyopathy. Ischemic cardiomyopathy mainly occurs in the long-term myocardial ischemia, resulting in diffuse myocardial fibrosis. This in turn affects the cardiac ejection function, resulting in a significant impact on myocardial systolic and diastolic function, resulting in a decrease in the cardiac ejection fraction. The pathogenesis of ICM is closely related to coronary heart disease. Mainly due to coronary atherosclerosis caused by coronary stenosis or vascular occlusion, causing vascular inflammatory lesions and thrombosis. As the disease progresses, it leads to long-term myocardial ischemia and eventually ICM. The pathological mechanism is mainly related to the mechanisms of inflammation, myocardial hypertrophy, fibrosis and vascular remodeling. Mitochondria are organelles with a double-membrane structure, so the composition of the mitochondrial outer compartment is basically similar to that of the cytoplasm. When ischemia-reperfusion induces a large influx of calcium into the cell, the concentration of calcium ions in the mitochondrial outer compartment also increases. The subsequent opening of the membrane permeability transition pore in the inner mitochondrial membrane and the resulting calcium overload induces the homeostasis of cardiomyocytes and activates the mitochondrial pathway of apoptosis. Mitochondrial Quality Control (MQC), as an important mechanism for regulating mitochondrial function in cardiomyocytes, affects the morphological structure/function and lifespan of mitochondria. In this review, we discuss the role of MQC  in the pathogenesis of ICM and provide important evidence for targeting MQC for ICM. ICM is a special type or late stage of coronary heart disease. It is mainly due to the long-term ischemia/hypoxia caused most commonly by coronary atherosclerosis, which leads to myocardial hypertrophy or stiffness, congestive heart failure and/or arrhythmia The pathogenesis of ICM involves coronary artery stenosis caused by atherosclerosis, which affects the supply of blood oxygen, but its essence is inflammatory The explosive inflammatory response can cause great injury to myocardium Cardiomyocyte necrosis and apoptosis is accompanied by inflammatory reaction. This pro-inflammatory stage aims to remove damaged cardiomyocytes or vascular endothelial cells. However, in the process of removing damaged cells and promoting wound healing may lead to excessive activity of fibroblasts and replacement of cardiomyocytes with active fibroblasts, resulting in scar formation or myocardial fibrosis, which is also one of the reasons for serious myocardial fibrosis and myocardial hypertrophy are seen in later stages of ICM The inflammatory mechanism regulating NLRP3 is closely related to mitochondria, which play a key role in the initiation and regulation of NLRP3 inflammatory bodies or inflammasomes. NLRP3 activation can further induce mitochondrial homeostasis imbalance, induce NLRP3 de‑ubiquitination and the release of mitochondrially derived molecules and destroy mitochondrial DNA It appears that mitochondria not only regulate NLRP3 activation, but are also the docking site for inflammatory body assembly. In stress stimulated cells, NLRP3 is activated and associated with mitochondria and mitochondrial associated membranes (MAMs) Current evidence suggests that mechanism regulating inflammatory is an important pathological factor contributing to ICM, and ROS bursts and NLRP3 activation mediated by stress-induced mitochondrial dysfunction may be key factors inducing ICM inflammation. Mitochondria may act as a “Trojan horse” to induce inflammatory storms, but they have dual regulatory roles, as can maintain the basic function of cardiomyocytes in the context of oxidative stress and inflammation Oxidative stress is defined as tissue destruction caused by an imbalance between ROS production and cell redox, which will have a variety of negative effects on the metabolic function and physiological activities of cardiomyocytes ROS are short-lived, low-molecular weight compounds, mainly derived from various redox reactions. Increases in ROS can alter cell signaling proteins and produce corresponding functional consequences that mediate the pathophysiological process of ICM Under normal physiological conditions, ROS are rarely produced in the heart. Superoxide leaking from the mitochondrial electron transport chain is quickly reduced to water and molecular oxygen by the antioxidant enzyme system. The heart can cope with redox changes and shows a significant adaptive response to maintain normal contractility. Mitochondria are the “hub” of cell redox process. Many mitochondrial stress signals participate in intercellular signal transduction and interaction mechanisms to regulate adaptation of cardiomyocytes to exogenous and endogenous stimuli. Oxidative stress is sensed by mitochondria, which initiate the release of stress signals that regulate membrane polarization, adenine nucleotide levels, ROS production, excitation/contraction coupling and opening/closing of membrane permeability transition pores 2+-ATPase (SERCA2a) and sarcolemmal (Na+ K+) Ca2+-ATPase, which results in decreased Ca2+ efflux and increased Ca2+ influx, ultimately leading to intracellular Ca2+ overload and cell death As shown in Figure ROS mediated mitochondrial dysfunction is particularly damaging to the coronary vascular system, as the amount of oxygen delivered to the myocardium is greater than to other tissues or organs. The development of ICM increases the duration of myocardial ischemia and can lead to necrosis. Although early reperfusion can restore blood flow to the affected area, the myocardial injury caused by reperfusion injury may be much higher than that caused by ischemia itself. This is in large part because reperfusion may induce the explosive ROS production, and the resultant oxidative stress injury to the myocardium may be more serious than the ischemic injury The cell death seen in patients with ICM has significant prognostic value with respect to cardiac function, quality of life and survival after coronary revascularization. Although numerous animal studies and clinical investigations have been performed to explore the appropriate detection modalities for cardiomyocyte death  stress or extracellular signals. Mitochondrial dysfunction promotes the leakage of mitochondria-localized pro-apoptotic factors  into cytosol stimulating activation of caspase-3/-9. ER stress is an adaptive response to attenuate at the transcription level the buildup of abnormal proteins within the ER. However, uncontrolled ER stress augments the expression of caspase-12, which contributes to caspase-3 activation. In addition to organelle-mediated apoptosis, extracellularly stimulated apoptosis is initiated via the death receptor 2+-calmodulin-dependent protein kinase (CaMKII) is another phosphorylation substrate of RIPK3 Necrosis accounts for only about 90,000 cardiomyocyte deaths 2 h after coronary artery occlusion and has no effect on the non-ischemic myocardium. Interestingly, necroptosis, a regulated form of necrosis, reportedly accounts for more than 50% of cardiomyocyte death during acute myocardial ischemia. Necroptosis is primarily induced by the activation of intracellular serine/threonine kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3 as a result of inflammatory responses or oxidative stress It appears that levels of both RIPK3 and phospho-MLKL are significantly upregulated in ischemic cardiomyocytes. Genetic or pharmacological blockade of necroptosis pathway molecules increases resistance to ischemic challenge and reduces infarct size, with a prominent improvement in cardiac function At later stages, ICM is accompanied by myocardial hypertrophy and heart failure, which are closely related to myocardial fibrosis. Myocardial fibrosis is an important part of tissue repair after myocardial ischemic injury. It is the result of persistent and repeatedly aggravated myocardial ischemia and hypoxia caused by coronary stenosis The interaction between fibroblasts and cardiomyocytes plays an important role in the course of myocardial fibrosis. Myofibroblasts can induce and regulate cardiomyocyte hypertrophy under stress or myocardial injury. Cardiac fibroblasts and cardiomyocytes interact through biochemical mediators such as TGF-β, angiotensin II (Ang-II) and various interleukins Excessive deposition of ECM within heart tissue leads to hardening of the fibrotic tissue and reduces the compliance of the myocardium. The purpose of fibrosis is to promote or accelerate deposition of connective tissue to maintain the integrity and structure of injured myocardial tissue. However, This adaptive response gradually leads to scarring of the damaged tissue Mitochondrial-derived ROS (mtROS)-induced TGF-β binds to cell surface receptors, leading to phosphorylation of the Smad transcription factor family to initiate gene expression, which may be a key factor in the proliferation and/or differentiation of fibroblasts. TGF-β-induced gene expression in fibroblasts requires mtROS produced by complex-III, and excessive accumulation of ROS can be detected in the mitochondrial matrix and cytoplasm. Application of antioxidants that target mtROS produced by complex-III reduces TGF-β-induced expression of pro-fibrotic genes 2+ homeostasis is closely related to the pathogenesis of ICM. Ca2+ overload within cardiomyocytes can be induced by inflammatory responses, oxidative stress injury and mitochondrial dysfunction, and can stimulate progression of both myocardial fibrosis and myocardial hypertrophy 2+ distribution is uneven within the myocardium. In many cell types cytosolic free Ca2+ acts as a second messenger transducing signals from extracellular stimuli. In cardiomyocytes at rest, the cytosolic Ca2+ concentration in cardiomyocytes is tightly regulated to around 10-7-10-8 mol/L through the action of SERCA2a and sarcolemmal (Na+ K+) Ca2+-ATPase. Transient changes in the level of cytosolic Ca2+ within cardiomyocytes and vascular smooth muscle mediate excitation-contraction coupling in these cells. Therefore, levels of cytosolic Ca2+ are strictly regulated 2+concentration by increasing extracellular Ca2+ influx through opening of Ca2+channels in cell membrane and Na+/Ca2+ exchange and release of Ca2+ from intracellular stores in the sarcoplasmic reticulum. Within the ischemic myocardium excessive influx of extracellular Ca2+ and release of store Ca2+ can lead to Ca2+ overload 2+ overload can lead to increased total peripheral blood flow resistance and hypertension, and gradually destroy the structural integrity of arteries and arteriolar walls. Vascular Ca2+ overload exacerbates arteriosclerosis in various animal models and coronary plaques in human, thereby contributing to the pathogenesis of ICM Dysregulation of Ca2+ dysregulation and injury 2+ concentration by interacting with the endo/sarcoplasmic reticulum (ER/SR) through “mitochondria ER contacts.” The molecular assembly that forms this connection provides a local environment that enhances the exchange of Ca2+ and other signals between the two organelles. Consequently, ischemia will not only cause mitochondrial oxidative stress damage, but also induces ER/SR stress, which leads to release of Ca2+ from the ER/SR into the mitochondria causing mitochondrial Ca2+ overload 2+ overload Mitochondria are the energy suppliers for cells. They also monitor signals from the extracellular and intracellular environment, including growth factors, ROS and DNA damage signals. In the animal models of ICM, mitochondrial dysfunction is a key factor contributing to myocardial Ca2+ and intracellular Ca2+ signaling, mitochondrial Ca2+ uptake also plays key role in regulating ATP production, autophagy, and cell death. Ca2+ is taken up into mitochondria primarily via mitochondrial calcium transporter. Dysregulation of mitochondrial Ca2+ homeostasis may trigger the opening of mPTPs in the inner membrane, which can lead to uncoupling of oxidative phosphorylation, mitochondrial swelling and mitochondrial inner or outer membrane damage Mitochondria are formed by a double membrane. The inner membrane contains the components involved in oxidative phosphorylation (ATP production), while the outer membrane controls mitochondrial dynamics, including their fission and fusion. In addition to helping to control levels of cytosolic Ca2+ homeostasis is closely related to ROS-mediated oxidative stress. The redox balance within cardiac and vascular myocytes is governed by the balance between ROS production and the activities of antioxidant enzymes. Although the relationship between oxidative stress and Ca2+ overload associated with ICM remains to be further clarified, ROS formation under various experimental and clinical conditions may directly or indirectly disrupt intracellular calcium homeostasis 2+ channels in both the SR and plasma membrane, resulting in extracellular Ca2+ influx and SR Ca2+ release. As mentioned earlier, upon reperfusion of the coronary artery and myocardium, the large influx of oxygen molecules into the ischemic tissue can also lead to the explosive production of ROS and myocardial mitochondrial damage. This will adversely affect mitochondrial oxidative phosphorylation, resulting in a lack of cell energy, which will, in turn, lead to SERCA dysfunction and release of excessive levels of Ca2+ from the SR, mitochondrial Ca2+ overload, and activation of apoptosis-related signaling In the pathogenesis of ICM, intracellular Ca2+ homeostasis  and feedback signals all acting in concert in a non-equilibrium steady state. The role of mitochondrial oxidative phosphorylation in the heart is to maintain the high phosphorylation potential to replace ATP catabolized during systolic/diastolic cycling The mitochondrial energy metabolism system perfectly adapts ATP synthesis to ATP hydrolysis, which is closely related to the integrity of mitochondrial morphology and structure and the normal maintenance of energy metabolism. Because the structure, function and energy metabolism level of mitochondria directly affect the metabolic processes of cardiomyocytes, MQC is an essential regulatory factor governing the survival cycle of cardiomyocytes. Myocardial energy consumption mainly depends on oxidized fatty acids, glucose, lactic acid, and ketones, which are used to produce ATP through oxidative phosphorylation. However, this is not absolute and related to the metabolic, nutritional, and stress state of the body +) exacerbating cardiomyocyte damage Mitochondria are where sugars, fatty acids and amino acids are oxidized to release the energy used for oxidative phosphorylation during ATP production. More than 95% of ATP in the mitochondria is produced through oxidation. Under normal physiological conditions, 60-90% of myocardial ATP is produced by the oxidation of fatty acids. The common pathway for final oxidation and oxidative phosphorylation is the tricarboxylic acid cycle 2+ and other ion homeostasis. At the same time, there is a loss mitochondrial energy metabolism and mitochondrial membrane potential. As a result of the decrease in oxidative phosphorylation, ATP synthesis is insufficient, and the cell death program is initiated. During reperfusion, the oxygen and nutrient supplies are recovered, but the supply exceeds the metabolic ability of cardiomyocytes, which the accumulation of mitochondrial ROS and an increase in mitochondrial membrane potential, which stimulates abnormal opening of mPTPs. In addition, the overactivation of oxidative phosphorylation and the tricarboxylic acid cycle leads to excessive ATP and ROS production and, ultimately, mitochondrial dysregulation and oxidative stress damage As shown in Figure In addition, the dysregulation of mitochondrial dynamics, mitophagy and biosynthesis caused by acute ischemia and reperfusion directly affects the cell metabolism and death processes. It has been observed, for example, that feeding mice a high-fat diet  activates mitophagy, which alters cardiac mitochondrial energy metabolism and fatty acid oxidation and indirectly affects the synthesis of mitochondrial DNA. However, blocking parkin-mediated mitophagy leads to mitochondrial dysfunction and lipid accumulation, exacerbating myocardial injury and cardiac systolic/diastolic dysfunction Hexokinase II (HK-II) catalyzes the first step in glucose metabolism in cardiomyocytes and is deeply involved in mitochondrial energy metabolism. Moreover, HK-II also acts as a signaling molecule that suppresses cell death mediated via the mitochondrial pathway. During myocardial ischemia, HK-II serves as a sensor of metabolic disorder that enhances mitophagy to maintain basic energy metabolism and resist stress-induced mitochondrial damage Cardiomyocyte hypertrophy refers to increases in cardiomyocyte volume, diameter, width or length and the number of sarcomeres. Cardiomyocyte proliferation occurs when myocardial hypertrophy is excessive, which a key reason for myocardial hypertrophy and heart failure seen in the late stages of ICM The contractile proteins within cardiomyocytes include myosin, actin and tropomyosin. Experiments show that when the heart is stimulated by increased load, or the heart is hypertrophic, long-term excessive pressure and/or load can lead to contractile protein dysfunction and increased ventricular wall stress, resulting in myocardial hypertrophy In 3-week- and 6-month-old cardiac hypertrophy model mice, mitochondria exhibit an abnormal structure with increased numbers of smaller than normal mitochondria. Expression of mitochondrial DNA coding genes is inhibited, and mitochondrial ATP is reduced MQC disorders not only lead to cardiomyocyte hypertrophy, but also contribute to myocardial fibrosis Cardiomyocyte inflammatory response plays an important regulatory role in the pathological mechanism of ischemic cardiomyopathy. It can directly affect the apoptosis or necroptosis program of cardiomyocytes and cause severe myocardial damage. We have previously reported the important regulatory role of inflammasome NLRP3 and mitochondria in ICM. In a mouse model of heart failure with preserved ejection fraction (HFpEF), mitochondria exhibit increased acetylation, and NLPR3 inflammasome assembly is increased on the hyperacetylated mitochondria. In addition, excessive production of IL-1β/IL-18 and severe myocardial fibrosis also appeared. Increases in β‑hydroxybutyric acid levels can attenuate the NLPR3 inflammasome formation, mitochondrial dysfunction and myocardial fibrosis caused by overexpression of pro-inflammatory cytokines. The interaction of mitochondrial hyperacetylation and inflammation is a key driver of the pathogenesis of HFpEF Studies have also shown that mitochondrial DNA released from autophagic cardiomyocytes promotes inflammatory responses mediated via Toll-like receptor (TLR-9) and can induce severe myocardial damage. Consistent with that finding, the myocardium of DNase II-deficient mice showed inflammatory cell infiltration and increased expression of inflammatory cytokine messenger RNA, and autolysosomes within the myocardium show deposition of mitochondrial DNA. TLR-9 knockout reduces the severity of the myocardial inflammation seen in DNase II-deficient mice MQC also indirectly affects inflammatory responses in rat cardiomyocytes. During LPS‑induced inflammation, STE20-like protein kinase 2 (MST2) mediates the up-regulation the mitochondrial fission genes Drp1, Mff and Fis1. This effect was associated with leading to reductions in mitochondrial ATP production, dysregulation of mitochondrial respiratory chain, increased mitochondrial oxidative stress, loss of membrane potential, and increased mitochondrial fragmentation. In addition, expression levels of IL-2, IL-8, MMP9, and Caspase-3/9 mRNA and protein are all increased. Also contributing to these effects was the interaction between Drp1 and Fis1 can alter mitochondrial dynamics within cardiomyocytes. Pretreatment with the MST2 inhibitor XMU-MP1 or inhibition of the Drp1-Fis1 interaction significantly reduces the mitochondrial fission and release of inflammatory factors, enabling mitochondrial homeostasis and cardiomyocyte activity to be maintained mt under those conditions have not yet been elucidated. In a preliminary study, we found that mitophagy and the UPRmt enable mitochondrial energy metabolism and respiratory chain function to be maintained under stress, ensuring an energy supply for cardiomyocytes. It has also been observed that in LPS-treated cardiomyocytes, urolithin A increases mitophagy, reduces mitochondrial fragmentation, restores the mitochondrial membrane potential, inhibits excessive production of mitochondrial ROS, and significantly reduces the inflammatory injury of cardiomyocytes The studies summarized above indirectly confirm the regulatory function of MQC in cardiomyocytes under inflammatory stress, though the regulatory functions of mitophagy and the UPRmt by oligomycin reduces the mitochondrial injury and myocardial dysfunction. After FUNDC1 knockdown using targeted siRNA, mitophagy was inhibited, but UPRmt was not blocked. We therefore suggest that endogenous UPRmt is a downstream regulator of mitotic phagocytosis, serving as a supplementary regulator to maintain mitochondrial homeostasis and suppress myocardial inflammatory injury when mitophagy is inhibited. Mitophagy and UPRmt may thus play synergistic regulatory roles after inflammatory injury to cardiomyocytes and serve as complementary regulators protecting mitochondrial structure and function in cardiomyocytes under inflammatory stress Interestingly, enhancement of endogenous UPRMitochondrial biogenesis may also play a regulatory role after inflammatory injury to cardiomyocytes. Sirtuin-3 (SIRT3) and AMPK indirectly stimulate mitochondrial biogenesis, thereby increasing mitochondrial renewal and cardiomyocyte functionality. In LPS-treated cardiomyocytes, the inflammatory responses are associated with decreases in SIRT3 and AMPK levels, which are followed by mitochondrial respiratory chain dysfunction, mitochondrial oxidative stress, and abnormal opening of mPTPs, as well as inhibition of PGC1α, Tfam and NRF2 expression and activation of caspase‑3. Conversely, overexpression of SIRT3 activates AMPK, improves mitochondrial redox balance and respiratory chain function, and increases expression of PGC1α, Tfam and NRF2 2+ overload, expression of inflammatory factors, and cell apoptosis. Because the myocardium is rich in mitochondria and mitochondria are the main producers of ROS In hears affected by ICM, cardiomyocytes produce large amounts of extracellular matrix and ROS. The oxidative stress caused by the excessive accumulation of ROS leads to alterations in cell membrane permeability and, in turn, CaAs shown in Figure In patients with late stage acute myocardial ischemia as well as mice with heart failure induced by TAC, AMPK2α is converted to AMPK1α. In addition, PINK-mediated reductions in mitophagy and mitochondrial function are accompanied by oxidative stress damage and cardiomyocyte apoptosis. By increasing PINK-mediated mitophagy and improving mitochondrial function, cardiac overexpression of AMPK2α prevents the development of TAC-induced heart failure. By contrast, AMPK2α-/- mutant mice showed early progression of TAC-induced heart failure that was worsened by reducing cardiac mitophagy. Increasing cardiac mitophagy resulted in elimination of damaged mitochondria, improved mitochondrial function, and reductions in ROS production and cardiomyocyte apoptosis. It appears that AMPK2α- and PINK1-mediated mitophagy is a crucial regulatory mechanism that inhibits the progression of heart failure After 8 minutes of KCl-induced cardiac arrest in C57BL/6 wild-type mice, Drp1 translocates to the mitochondrial membrane, resulting in increased mitochondrial fission, and lactate and ROS production, and oxidative damage. Administration of Mdivi-1 during cardiopulmonary resuscitation can inhibit Drp1 activation, preserve mitochondrial morphology, reduce oxidative damage, and enhance myocardial function after spontaneous circulation is restored It also appears that insulin-like growth factor II (IGF-II), acting via its receptor IGF-IIR on cardiomyocytes, can also trigger mitochondrial dysfunction, mitochondrial ROS accumulation, oxidative stress damage, and mitochondrial disruption that leads to the formation of autophagosomes. The loss of mitochondrial contents increases levels of Parkin-dependent mitophagy and initiates the cell death program via the cytochrome c pathway 2+ homeostasis. It is known that increases in intracellular Ca2+ can lead to activation of phospholipases, degradation of membrane phospholipids and increases membrane permeability that enable extracellular Ca2+ to flow into the cell down its concentration gradient and exacerbate Ca2+ overload 2+ pump and SERCA, thereby inhibiting removal of the excessively high cytosolic Ca2+MQC is also involved in the regulation of Ca2+ transfer from the ER to the mitochondria, which could potentially cause mitochondrial Ca2+ overload 2+ uptake. This suggests that Mfn2 is a key mediator of Ca2+ transport between the ER and mitochondria and that Mfn2 is also an important regulator involved in maintaining Ca2+ homeostasis in cardiomyocytes under stress, which may explain why under some conditions Mfn2 mediates Ca2+ overload and cell death. Mfn2-deficient mice exhibit moderate cardiac hypertrophy with slight deterioration in cardiac function. However, the lack of Mfn2 increases the likelihood of Ca2+ overload, abnormal opening of mPTPs, changes in mitochondrial structure or morphology, and cell death The distribution of Mfn2 within cells is not limited to the outer mitochondrial membrane, as it has also been detected in the ER membrane. The dual positioning of Mfn1 in the ER and mitochondrial membranes is thought to facilitate CaCell death is the process by which multicellular organisms clear infected, damaged, or dysfunctional cells, and a way for the body to renew itself. This process can help a healthy myocardium clear damaged cells. However, the stressed myocardium, MQC disorders (such as excessive mitophagy) also can activate the cardiomyocyte death program 2+ overload may occur. The balance between mitochondrial fusion and fission is disrupted, and Drp1 drives mitochondrial fission. In cardiomyocyte-specific Drp1 KO mice, mitochondria are elongated and there is accumulation of damaged mitochondria due to a decrease in mitophagy, which leads to increases in apoptosis. The severe mitochondrial dysfunction is also accompanied by left ventricular dysfunction, with some mice dying within 13 weeks MQC is able to fully participate in the process of cardiomyocyte death (including apoptosis or necrosis). Under stressful conditions such as ischemia/hypoxia intracellular ROS will be overproduced and CaIt was also found that the specific deletion of Mfn2 from cardiomyocytes leads to accumulation of autophagic lysosomes and fusion of autophagosomes and lysosomes, while cardiac-specific Mfn2 KO mice exhibit dysregulation of mitochondrial energy metabolism. In addition, Mfn2 knockdown using targeted siRNA prevented autophagic lysosomal fusion in cardiomyocytes and increased the cells' susceptibility to ischemia-reperfusion. This suggests that not only does Mfn2 regulate mitochondrial fusion/fission, it also supports mitophagy in cells subjected to ischemic stress by mediating mitophagic lysosome fusion In addition to disrupting mitochondrial structure and function, hypoxia/ischemia induces AMPK activation. Stimulation of AMPK activity using the AMP analog AICAR increases mitophagy and blocks the mitochondrial apoptosis pathway. Conversely, blocking AMPK activation suppresses mitophagy and increase of cardiomyocyte apoptosis We previously showed that FUNDC1 is a mitophagy receptor that interacts with LC3II to mediate mitophagy and regulate the number and quality of mitochondria in response to hypoxia‑induced cardiomyocyte injury. Under hypoxic stress, FUNDC1 can triggers mitophagy in platelets from wild-type mice. In cardiac-specific FUNDC1 KO mice, cardiac function is reduced and infarcted areas are larger following myocardial infarction. Hypoxic preconditioning can induce FUNDC1-dependent mitophagy and suppress cardiomyocyte death DUSP1 expression is down-regulated after acute cardiac ischemia/reperfusion injury. Compared to wild-type mice, DUSP1 transgenic mice also show a smaller infarct size and better cardiac function. DUSP1 deficiency promotes JNK activation, which enhances expression of Mff and promotes phosphorylation/activation of Bnip3. This increases mitophagy levels, and a large number of mitochondria to be cleared, resulting in insufficient mitochondrial ATP production and activation of caspase-3/-9-mediated cardiomyocyte apoptosis. Interestingly, reintroduction of DUSP1 attenuates Mff/Bnip3 activation, inhibit the mitochondrial fission and mitophagy, and reduce cardiomyocyte apoptosis During the onset of ICM, the structure and function of coronary blood vessels undergo pathological changes that include thickening and hardening of arterial walls, dilatation of the vascular lumen, thickening of the arterial intima, and vascular calcification Under physiological conditions, vascular cells, and especially vascular endothelial cells, are a dynamic balance of regeneration, growth, degradation and death. In the process of cardiovascular disease or aging, blood vessels are degenerating and dying, and the ultrastructure of vascular endothelial cells are significantly altered. Aging vascular endothelial cells become flattened and widened, cell gaps also widen, intracellular ROS production increases, cell permeability increases, and macromolecular substances enter the intima from the plasma, resulting in abnormal endothelial cell function and impaired endothelium-dependent vasodilation, which eventually leads to vasospasm, thrombosis, macrophage infiltration, and inflammatory responses 2+ overload can lead to vascular injury Mitochondria are present in all vascular cell types, where they play important roles regulating tissue repair, apoptosis, and a variety of physiological and pathological processes. As shown in Figure Activation of mitochondrial fission mediated by Drp1 and excessive production ROS in endothelial cells cause oxidative stress and endothelial dysfunction 2+ deposition and vascular calcification. We also observed that in WT mouse endothelial cells, NR4A1 activates CK2α, promotes Mff phosphorylation, and enhances translocation of Drp1 to mitochondria, leading to excessive mitochondrial cleavage and disruption of mitochondrial structure and function and, ultimately, accumulation of damaged mitochondria and apoptosis. Deleting NR4A1 reverses these effects, enabling stable mitochondrial structure and function to be maintained and protecting against acute microvascular injury, which enabled vascular function and endothelial cell activity to be maintained Selective mitophagy can reverse endothelial-dependent relaxation dysfunction that increases arterial stiffness in aging blood vessels by altering the total redox state of the vessels through inhibition the ROS production. Mitophagy inhibition exacerbates the vascular injury caused by oxidative stress, and interaction of fibrosis with mitochondrial fission inhibition is a key factor leading to vascular remodeling The cardiac microvasculature is composed of coronary arteries with diameters ranging from 100-400 μm and capillaries with diameters less than 10 μm In ICM patients, microvascular damage generally occurs in necrotic or infarcted areas within the myocardium, so re-establishing blood flow may not yield improvement of the patient's condition. However, restoring flow can enable transmission of nutrients to the necrotic area, speeding up healing, reducing infarct expansion, delaying left ventricular remodeling, and promoting formation of new microvessels Microvascular endothelial cells cover the inner wall of blood vessel and are in direct contact with the bloodstream. They are usually in a differentiated and static state but under the action of angiogenic factors, they change from a differentiated to an undifferentiated state. The functions of microvascular endothelial cells include reducing vascular permeability, regulating material exchange between tissue and blood, maintaining blood fluidity by balancing anticoagulant/fibrinolytic systems and antiplatelet functions, and regulating vasoconstriction/relaxation by releasing vasoconstrictor and diastolic factors 3R, and XO is enhanced, which leads to oxidative stress injury, Ca2+ overload, and mitochondrial swelling/deformation, and eventually vascular endothelial cell apoptosis initiated via the mitochondrial pathway In an earlier literature summary, we explained that RIPK3-mediated apoptosis is the primary factor contributed to the pathogenesis of myocardial ischemia-reperfusion injury. RIPK3 is also an important regulator endothelial cell apoptosis. Following ischemia-reperfusion, vascular endothelial expression of RIPK3, IP2+ overload is related to RIPK3-mediated ER stress. Deletion of RIPK3 reduces expression of adhesion molecules and various inflammatory factors and reduces endothelial swelling and apoptosis, which enables the patency of the microvascular system to be maintained 2+ homeostasis, and inhibit abnormal activation of the MCU and opening of mPTPs In an experimental study of myocardial ischemic injury, we confirmed that RIPK3 migrates to SR, causing in stress injury in cardiomyocytes. It is therefore likely that the endothelial CaFor ICM patients, poor lifestyle is an important factor that affects the pathological mechanism and pathogenesis of the disease. As mentioned before, sedentary lifestyles, smoking and other bad lifestyles can to varying degrees directly and indirectly cause vascular damage or blockage, becoming important pathogenic factors for ICM From the perspective of mitochondrial redox balance, exercise or training can increase the activity of antioxidant enzymes and improve the ability of GSH, GST and GSH-Px to scavenge free radicals Exercise has beneficial effects on age-related damage to mitochondrial biogenesis and dynamics and reductions of mitophagy. As a result, exercise may have an impact on crucial cell signaling pathways involved in maintaining mitochondria quality and quantity in the elderly. Although several exercise programs are known to improve mitochondrial structure and function, further research is needed to better understand the cell signaling pathways involved in the control of mitochondrial quality and quantity. Several exercise programs are known to modify mitochondrial activity and turnover, but additional study is needed to precisely determine the interaction mechanism between mitochondrial function, aging and physical activity, as well as the factors affecting mitochondrial function From the perspective of MQC, exercise maintains mitochondrial function and cardiomyocyte activity by promoting the clearance of dysfunctional mitochondria through mitochondrial biogenesis and mitophagy. Moderate exercise can cause mitochondrial oxidative stress and promote the mitophagy to remove damaged or dysfunctional mitochondria and maintain cell homeostasis. Moderate and heavy exercise have a two-way regulatory effect on mitochondrial fusion and fission In recent years, research has provided variety of drugs, such as the mitochondrially targeted antioxidant MitoQ, that exert protective effects on cardiomyocytes and endothelial cells by affecting the regulation MQC and mitochondrial homeostasis and mitigating myocardial injury after infarction 2+ homeostasis, which disrupts energy metabolism. Interestingly, MCU activation eliminates the cardioprotection provided by melatonin, which results in disruption of mitochondrial structure and function in cardiomyocytes. It thus appears the negative effects of renal ischemia/reperfusion injury on myocardial vitality and cardiac function are related to IP3R phosphorylation, MCU upregulation, and Ca2+ overload. Melatonin protects heart function from CRS-3 by inhibiting IP3R-MCU signaling Melatonin is also able to influence MQC and SR homeostasis through BAP31 and reduce LPS-mediated myocardial inflammatory damage. It does this by supporting mitochondrial function and inhibiting ER/SR stress, which improves cardiomyocyte viability. On the other hand, inhibition of the ERK pathway and BAP31 reduces melatonin's ability to affect mitochondrial function and ER/SR homeostasis under LPS stress 616 phosphorylation and increases Drp1 S637 phosphorylation, which ultimately inhibits mitochondrial fission and restores mitochondrial function Several drugs used to treat or prevent the myocardial microvascular injury target the MQC. These include empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has been shown to have a cardioprotective effect. We observed that empagliflozin improves the structure and function of the diabetic myocardium, in part by inhibiting cardiac microvascular endothelial cell senescence as well as the production of mitochondrial ROS and the resultant oxidative stress, thereby protecting the barrier function of cardiac microvascular endothelial cells. Empagliflozin also supports eNOS phosphorylation and endothelial-dependent relaxation and improves microvessel density and perfusion. What's more, it triggers AMPK activation, inhibits Drp1 SIn addition, the mitochondrial fission inhibitor Mdivi-1 protects the myocardium by affecting the regulation of the mitochondrial fission/fusion. By inhibiting excessive mitochondrial fission during ischemia/reperfusion injury, Mdivi-1 preserves the integrity of mitochondrial structure and function in cardiomyocytes and reduces infarct area after myocardial infarction We also observed that quercetin, an active ingredient in various natural medicines, protects human cardiomyocytes subjected to hypoxia/reoxygenation. Quercetin pretreatment inhibits H/R‑mediated ROS production and oxidative stress. In addition, quercetin increases mitophagy, up-regulates transmembrane BAX inhibitor-1 motif containing 6 (TMBIM6) mRNA and protein expression, which preserves mitochondrial energy metabolism and suppresses the SR stress in human cardiomyocytes. These protective effects of quercetin are blocked by SIRT1 knockdown using targeted siRNA In this review, we summarized the clinical symptoms, disease manifestations at different stages, and epidemiological characteristics of ICM. The incidence of ICM is related to unhealthy lifestyle habits, including smoking, lack of exercise, and a high-fat/high-sugar diet. At present, substantial progress has been made in our understanding of ICM and mitochondrial. Although the medical community has some understanding of the mechanism underlying the abnormal mitochondrial contributing to the occurrence and development of acute myocardial injury after myocardial infarction or ischemia/reperfusion, the pathological mechanism of coronary microvascular/microcirculation injury or dysfunction after acute ischemia/reperfusion has not yet been clarified, and there is a need for further research into relevant targeted therapeutic drugs. It will involve both animal and cell experiments and translational studies that explain the mechanism underlying the clinical features of coronary microvascular injury. This highly important, as coronary microvascular injury is a crucial driver of the occurrence and development of ICM. In addition, the roles of mitochondrial biosynthesis and the mitochondrial unfolded protein response in ICM is not well understood. It will therefore be necessary to conduct in-depth exploration of the mitochondrial quality detection system and directly connect ICM to ICM-related vascular injury. This could potentially serve as the basis for developing mitochondrially targeted strategies to improve myocardial and vascular function and provide a theoretical basis for the prevention and treatment of ICM and other vascular injury diseases.In this review, we endeavored to summarize mitochondrial quality monitoring and the pathological mechanisms responsible for the development and progression of ICM. The important contribution of abnormal MQC to the occurrence and development of vascular aging and aging-related cardiovascular diseases is now well established. At present, however, research mainly involves animal and cell experiments, though a few translational studies have shown the clinical relevance of these mechanisms to humans. In addition, little is known about the role of changes in mitochondrial dynamics in vascular aging. It is therefore necessary carry out a more in-depth exploration to establish the precise linkage between changes in MQC and vascular aging and aging-related cardiovascular diseases. It is anticipated this will provide a theoretical basis for the development of mitochondrially targeted strategies to improve vascular function as well as to prevent and treat ICM.This study is supported by the National Natural Science Foundation of China (No. 81902011)


In addition to showing antidiabetic effects, sodium–glucose cotransporter 2 (SGLT2) inhibitors also reduce cardiovascular events in patients with type 2 diabetes mellitus. In major trials of cardiovascular outcomes, SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes, including reduced rehospitalization in patients with heart failure, regardless of the presence of diabetes. A recent report showed that the benefits of SGLT2 inhibitors in terms of cardiovascular deaths/admissions caused by heart failure and reduced ejection fraction were greater in Asians than in Whites. In this review, the first part demonstrates the results of recent clinical trials and their clinical implications and outlines current trials and upcoming research areas. The second part provides a general overview of the current understanding of the mechanisms of the cardiovascular benefits of SGLT2 inhibitors.  •Type 2 diabetes mellitus and heart failure are closely related.•SGLT2 inhibitors can reduce the incidence of cardiovascular events and heart failure.•SGLT2 inhibitors can improve hemodynamics, myocardial energy supply, and sympathetic and parasympathetic nerve activities. Data from a pooled analysis including the DECLARE-TIMI 58 trial, the SOLOIST-WHF, and SCORED  trials showed borderline significant reduction in the composite outcome of HF hospitalization or cardiovascular death.In a pooled analysis, empagliflozin was shown to be well-tolerated by East Asian patients with T2DM considering an exposure of more than 2,100 patient-years, consistent with the results for the overall population tested.Dapagliflozin has been reported to reduce the risk of HF and direct medical costs in comparison with DPP-4 initiators in Asian countries.,The beneficial effects of SGLT2 inhibitors on hemodynamics, myocardial energy supply, and sympathetic and parasympathetic nerve activities are illustrated in ,,,The combination of the natriuretic and osmotic effects of SGLT2 inhibitors reduces intracellular and extracellular volumes to the same extent.,+/H+) exchange in the myocardium, resulting in an increase in mitochondrial calcium levels, improvement in mitochondrial function, reduction of oxidative stress, and reduction of arrhythmias.SGLT2 inhibitors increase the circulatory rates of ketone bodies.In our EMBODY trial, a prospective randomized placebo-control trial in patients with acute myocardial infarction associated with T2DM, the cardiac sympathetic nerve activity was significantly decreased, and the parasympathetic nerve activity was significantly increased in only the empagliflozin group.,SGLT2 inhibitors may increase the risk of fungal genital infections, urinary tract infections, and euglycemic diabetic ketoacidosis.SGLT2 inhibitors can be used for the secondary prevention of cardiovascular outcomes in patients with T2DM and a history of cardiovascular disease in consideration of their beneficial cardiovascular and metabolic effects. SGLT2 inhibitors can also be used for primary and secondary prevention of HF-related hospitalization in patients with T2DM and multiple risk factors.Dr Shimizu has received honorariums and/or scholarship funds from Boehringer Ingelheim Co, Ltd, Daiichi Sankyo Co, Ltd, Ono Pharmaceutical Co, Ltd, Bayer Co, Ltd, Pfizer Co, Ltd, and Bristol-Myers Squibb Co, Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


N = 28 research reviews that cover 248 primary studies spanning 50 years were included. Results: The majority of the included reviews addressed general internet and computer use (82% each) (RQ1). Of the 28 reviews, only one (4%) worked with a theoretical framework (RQ2) and 26 (93%) covered primary studies with quantitative-experimental designs (RQ3). The positive effects of technology use were shown in 55% of the outcome measures for loneliness and 44% of the outcome measures for social isolation (RQ4). Conclusion: While research reviews show that CTs can reduce loneliness and social isolation in older people, causal evidence is limited and insights on innovative technologies such as augmented reality systems are scarce.Background: Loneliness and social isolation in older age are considered major public health concerns and research on technology-based solutions is growing rapidly. This scoping review of reviews aims to summarize the communication technologies (CTs) (review question RQ1), theoretical frameworks (RQ2), study designs (RQ3), and positive effects of technology use (RQ4) present in the research field. Methods: A comprehensive multi-disciplinary, multi-database literature search was conducted. Identified reviews were analyzed according to the PRISMA  framework. A total of  The human population is ageing at a fast pace on a global scale. It is estimated that by 2030, one in six people in the world will be aged 60 years or over, and the share of the population aged 60 years and over will increase from 1 billion in 2020 to 1.4 billion in 2030 and 2.1 billion in 2050 , social networking site, videoconference system, other communication system); (m) theoretical framework of review (present or not present); (n) study design ; (o) outcome measures for loneliness and/or social isolation. The variables are used to describe the previous research reviews and to answer the four review questions.All quality assessment document (accessible via https://osf.io/huc6p/ (accessed on 5 September 2022) includes the following critical items: (a) item 2: establishment of methods previous to study conduction; (b) item 4: literature search strategy; (c) item 7: excluded studies; (d) item 9: risk-of-bias assessment; (e) item 11: statistical methods for meta-analysis; (f) item 13: risk of bias in individual studies; (g) item 15: publication bias assessment. As suggested by Shea et al. (2017), we did not compute an overall score by combining all individual item ratings. Instead, we first assessed which items were relevant for each specific review  and rated it accordingly. We then classified the reviews regarding overall confidence in the results. Our classification was obtained by assigning values to the fulfilled relevant quality criteria (presented as percentages). The quality of the included research reviews was classified as follows: (1) high = 75%–100% of all critical 7 items fulfilled, (2) moderate = 50%–74%, (3) low = 25%–49%, and (4) critically low = 0%–24%. Out of all N = 28 included reviews, 3 (11%) were considered to have high quality, 10 (36%) to have moderate quality, 3 (11%) to have low quality, and 12 (43%) to have critically low quality  . Given tlity see . While lN = 28 included reviews are displayed in The general characteristics of the Quantitative variables were coded as 1 (present) and 0 (not present) while open coding was used for qualitative variables. Variables for each review question were coded as follows: RQ1 (types of CT): Each technology was coded quantitatively. RQ2 : Theories were coded openly. RQ3 (study designs): Designs were grouped and coded quantitatively. Additionally, the number of primary studies in each design group was counted. RQ4 : The number of outcome measures for loneliness and/or social isolation within each review was coded quantitatively while the reported effects were described qualitatively. This review provides the sum of outcome measures for loneliness and the sum of outcome measures for social isolation instead of giving all reviews the same weight. Therefore, if a review comprises 10 individual primary studies and reports 5 outcome measures for loneliness and 5 outcome measures for social isolation, we decided to report said outcome measures separately instead of only reporting the review result as one individual result. This decision was made given that the number of included studies analyzing CT impact differed greatly from one review to another (between 1 and 41 studies per review). Therefore, reporting individual outcome measures as opposed to reporting 28 general review results with apparently the same weight was considered a more transparent and comprehensive approach.If an included review covered only primary studies addressing CT-related interventions and/or self-directed behaviors, the general conclusions of the review were used to report the effects.If an included review covered both CT-related and non-CT-related interventions and/or self-directed behaviors, only the technology-related effects were used to report the effect. The aforementioned technology-related effects were extracted from the results section, individual tables, or specific sections in the overall conclusions of the respective included reviews.The reported outcomes come from one of two sources, depending on the type of studies covered by the included reviews:We classified the outcomes as “positive effect” if a decrease in loneliness and/or social isolation or an association with lower levels of loneliness and/or social isolation was reported and as “negative effect” if an increase in loneliness and/or social isolation or an association with higher levels of loneliness and/or social isolation was reported. We coded “no effect” if no significant variation in loneliness and social isolation was reported and as “unclear effect” if no general conclusion related to effects of technology use on loneliness and/or social isolation was reported or the review stressed conflicting results (mixture of positive and no effects). All quantitative data are presented using absolute frequencies and/or percentages and all qualitative data are presented in narrative form. Given the nature of the scoping review, only descriptive statistics are used to present the data.To answer RQ1, a count of the technologies and the number of reviews covering them was performed and revealed the following main results: Internet and computer were the most researched communication technologies (23 reviews or 82% each), followed by videoconference systems such as Zoom or Skype , email , telephone , and social robot . Augmented reality (AR) or virtual reality (VR) systems were covered by only one of the 28 included reviews 4%; see . PRISM  is a special software for seniors created to support social connectivity, memory, and leisure activities 32]. AmonN = 28 included reviews, only one made use of a general theory at the review level  [Masi et al. (2011)  hypothesa (1986) .Most included reviews did not provide any theoretical framework and they acknowledged this as one of their main limitations. To answer RQ3, a count of study designs used in the included reviews was undertaken. Study designs were divided into four groups: qualitative designs, quantitative-observational designs, quantitative-experimental designs, and mixed-methods designs see . Qualitative designs were adopted in primary studies covered by 16 reviews. The included review with the highest number of included qualitative primary studies contained 24 qualitative primary studies [ studies  and the  studies . The mos studies .Quantitative-observational designs were used in primary studies covered by 19 reviews. Gardiner et al. (2018) [. (2018)  summariz. (2018)  covered Quantitative-experimental designs were applied in primary studies covered by almost all included reviews (26/28). Masi et al. (2011) [. (2011)  covered . (2011)  the loweMixed-methods designs were applied in the primary studies of 10 reviews. Of those reviews, Gasteiger et al. (2021) [. (2021)  and Hein. (2021)  covered . (2021)  covered outcome measures for loneliness and social isolation were mostly obtained through the application of standardized scales. The most used psychometric scales for loneliness were the UCLA  Loneliness Scale [For all quantitative studies, ss Scale  and the ss Scale . The UCLpsychometric scales for social isolation were diverse and none was used in a generalized manner across reviews. Measures included the Friendship Scale [The used ip Scale , the Lubip Scale , and theip Scale . TypicalTo answer RQ4, reported outcome measures for loneliness and social isolation are summarized in a table see  above asFrom a total of 41 CT-related outcome measures from individual studies reported for social isolation reduction, 44% (18/41) point to a positive effect of technology use. However, slightly more than half (55%) revealed no effect (5/41) or unclear effects (18/41) See .While the majority of reported outcome measures on loneliness (55%) point to positive effects in terms of loneliness reduction through communication technology use among older people, the minority of reported outcome measures on social isolation (44%) confirm positive effects.Several types of CTs have been studied in an effort to understand their potential positive impact on the reduction of loneliness and social isolation among older adults (RQ1). As evidenced by this scoping review of reviews, internet and computer use are the types of CT covered by most of the included reviews. However, the vagueness of the concepts and related measures makes it impossible to clearly understand which type of internet and computer use was associated with a reduction in loneliness or isolation. The CTs that were more narrowly defined and measured, such as the use of videoconference systems, email, social networking sites, or videogame consoles, were most often covered in previous reviews in the context of targeted interventions and only seldom in the context of self-directed behaviors. As more and more older adults adopt CTs in their everyday lives, it becomes more relevant to analyze CT use in relation to the reduction of loneliness and/or social isolation . HoweverThe lack of an overarching theoretical framework linking communication technology use and loneliness or social isolation reduction was evident in all reviews except one (RQ2). Although some reviews reported which theories were used to create certain individual targeted interventions, no comprehensive frameworks at the review level were used when summarizing CTs and their impact on loneliness and/or social isolation among older adults which is a limitation acknowledged by the reviews and highlighted in the methodology literature .Most of the included research reviews covered quantitative and even experimental designs, while qualitative and mixed-methods designs were not that prevalent (RQ3). Still, causal evidence is limited as primary studies as well as extant review studies suffer from limited methodological quality, as our AMSTAR 2 analysis of the included reviews has demonstrated. Positive effects of CT use were shown in 55% of the outcome measures for loneliness and 44% of the outcome measures for social isolation presented in the reviews summarized in this scoping review of reviews. Furthermore, there are some slight differences between the number of outcome measures showing positive effects compared to no effects or unclear effects from one study design to another; however, said differences are not substantial enough to be included in the global analysis of the study (RQ4). This can be characterized as an ambivalent overall result, as in roughly half of the cases, the intended positive effect of communication technology was not reached. This could be caused by deficits in theoretical assumptions, in the design of the communication technologies, or the usage of the CTs and/or study designs and instruments. The slightly more positive overall result for loneliness could indicate, for example, that issues of loneliness were addressed more sufficiently by technology use and/or that changes in loneliness were measured more precisely by adopting mainly one established instrument, namely the UCLA Loneliness Scale. Divergent and vague definitions of loneliness and social isolation, the interchangeable use of both terms, and unclear empirical differentiation, particularly in qualitative studies, are known problems in the research field ,17 that In general, most reviews conclude that further research is needed in order to decisively confirm the causal effects of CT use regarding the reduction of loneliness and/or social isolation among older adults. A call for conducting methodologically and theoretically robust studies is made in most reviews. However, conducting studies with older adults presents a specific set of challenges that need to be tackled. Recruiting older people can be difficult given that they are considered a hard-to-reach group. Additionally, age-related issues  cause studies involving older adults to have higher attrition levels. Furthermore, conceptual issues regarding concise classifications of CT use and a clear differentiation between loneliness versus social isolation need to be resolved. More theory work linking the characteristics of different communication technologies with processes of loneliness and social isolation reduction taking into consideration different types of communication partners, interaction tasks, and topics is necessary. This scoping review of reviews is not without its limitations. Firstly, only English-language reviews were considered during the screening process, possibly causing the exclusion of relevant reviews published in other languages.Additionally, there were some minor deviations from the exclusion criteria, namely age limit  and cognitive state . However, these deviations were so minor that excluding the whole review would have created an even stronger bias. The classification of CTs (according to main communication devices or main communication systems/applications) was adopted from the included reviews and has to be characterized as pragmatic. It is not an analytical classification; hence, the categories come with some vagueness and overlap, particularly in the broad categories of general “internet” use and general “computer” use. This problem could not be resolved in this review of reviews because it goes back to the vague measurement of communication technology use in the primary studies.Unfortunately, primary studies also are often vague about the key outcome measures of “loneliness” and/or “social isolation” reduction. Both terms were sometimes used interchangeably and therefore some inconsistencies in the reported outcome measures may have occurred, particularly in the qualitative studies. Finally, the AMSTAR 2 quality assessment tool is not an optimal fit for scoping reviews given that the objective of a scoping review is to include a broad spectrum of study designs and is not limited to systematic reviews and meta-analyses (which is the main focus of AMSTAR 2). However, the aforementioned tool is the best established and most used instrument for assessing research review quality and was therefore adopted for this scoping review of reviews.Among the research gaps identified in the present scoping review of reviews are theory development, the provision and use of validated measures particularly of social isolation, longitudinal study designs, and RCTs establishing causality. Furthermore, there was a notable absence of coverage of self-directed behaviors within the included reviews. More insights in said behaviors are needed to better understand how current and future generations of seniors adopt and use off-the-shelf communication technologies in self-directed ways to overcome loneliness and social isolation. Along the same lines, a focus on participatory and human-centered designs could benefit the development of future technologies being created especially for seniors. Although several custom-made CTs were developed and evaluated in the context of targeted interventions, these CTs are not commercially available and cannot be used outside respective research settings. Future projects, hence, should have an eye on the sustainability of innovative technological solutions and interventions. Finally, the adverse physical and psychological outcomes associated with loneliness and social isolation in old age make this study relevant for medical professionals and health institutions. With technologies becoming mainstream communication tools, an opportunity arises to understand which CTs could produce holistic positive effects by helping maintain social contacts and supporting societal participation of older adults. Additionally, the integrative potential of certain CTs could be harnessed through their adoption in clinical settings, assisted living facilities, and private homes where residents are unable to participate in social activities due to limited mobility or health issues. This scoping review of reviews—the very first to provide a complete systematic overview of the research field by mapping all studied CTs, theories, and study designs in the context of targeted interventions and self-directed behaviors—confirmed the positive associations of CT use with loneliness and social isolation reduction among older people. There is, however, limited causal evidence and a noticeable absence of innovative technologies in the reviewed literature. Nevertheless, the presented summary of established effects, as well as a clear assessment of the methodological quality of the included reviews, offer a solid starting point for further and future research in the field.


Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism. The adrenal gland is an endocrine tissue composed of two distinct zones with different functions: the cortex, responsible for steroid biosynthesis, and the medulla, where catecholamine biosynthesis occurs. In human, the adrenal cortex is subdivided into three distinct functional zones: the outer part of the adrenal cortex is formed by the zona glomerulosa (ZG) responsible for mineralocorticoid biosynthesis, the intermediate and thickest part is formed by the zona fasciculata (ZF), responsible for glucocorticoids biosynthesis, and the inner part is formed by the zona reticularis (ZR) responsible for the biosynthesis of adrenal androgens . Both adInterestingly, the adrenal gland is one of the most vascularized organs. It has been shown that this organized vascular network played an important role during embryogenesis to ensure adrenal growth and differentiation, but also during whole life to provide precursors necessary for the biosynthesis of steroid hormones and to allow their secretion in blood flow . The speKCNJ5, CACNA1D, CACNA1H, CLCN2) and ATPases  in up to 96% of APA  or increase intracellular calcium , leading to activation of calcium signaling that is the main trigger for aldosterone biosynthesis. In addition, mutations in CTNNB1 coding for β-catenin, à key regulator of adrenal cortex development and function, have been identified in a subset of patients with PA, either alone or in association with mutations of GNAQ/GNA11 in patients presenting with PA at puberty, pregnancy or menopause  is the most common form of secondary arterial hypertension due to autonomous aldosterone production from the adrenal cortex. The two major causes are unilateral aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia . Patients show increased blood pressure, often associated with hypokalemia. Diagnosis is made in the presence of suppressed renin levels and increased aldosterone to renin ratio and is confirmed by one of different suppression tests. Adrenal imaging and adrenal vein sampling allow to distinguish between unilateral and bilateral forms and to introduce optimal treatment, either adrenalectomy for APA or treatment with mineralocorticoid receptor antagonists for bilateral forms . PA is f% of APA . These menopause . Howeverenopause . This coIn this review we will briefly summarize the mechanisms regulating aldosterone biosynthesis in the adrenal gland, describe adrenal vascularization in normal conditions and how the cross-talk between the hormonal  and vascular  components ensures adrenal cortex growth and function under physiological conditions. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of PA.CYP11B2, which is specifically expressed in this zone. Regulation of aldosterone biosynthesis is aimed at maintaining its essential functions as one of the principal regulators of extracellular fluid and electrolyte homeostasis as well as blood pressure, due to its effects on sodium reabsorption and potassium secretion in the kidney. Thus, aldosterone biosynthesis is regulated by the renin-angiotensin system (RAS), potassium concentrations and, to a lesser extent, by the adrenocorticotropic hormone (ACTH) (via angiotensin II (AngII) binding to its type 1 receptor (AT1R) in ZG cells. This activates the inositol triphosphate pathway that stimulates Ca2+ release from the endoplasmic reticulum; alternatively, AngII inhibits potassium channels and the Na+,K+-ATPase, inducing cell membrane depolarization, followed by opening of voltage-gated calcium channels. Both pathways increase intracellular calcium concentrations and activate calcium signaling, which regulates different steps involved in aldosterone biosynthesis, including expression of CYP11B2 via calcium/calmodulin-dependent protein kinases  phosphorylation, thus increasing the amount of cholesterol delivered to the inner mitochondrial membrane. The conversion of cholesterol to pregnenolone in the mitochondria is one of the principal limiting steps in steroid biosynthesis  and activates adenylate cyclase (AC), with subsequent activation of downstream signaling pathways, in particular the cAMP-dependent protein kinase (PKA) pathway Figure 1ynthesis  catalyzeynthesis . In addiynthesis , 21.in vitro to activate aldosterone production  The arteriae medullae, responsible for medulla arterial supply after passing directly through the adrenal cortex; and 2) The arteriae cortices, that arise directly from the capsule plexus, form an anastomotic network in the ZG, then cross the ZF as longitudinal capillary sinusoids between the columns of ZF cells , 4. The The widely branched capillary bed of the adrenal cortex strongly suggests an interaction between endothelial cells (ECs) and adrenal epithelial cells , 47. Indvia AT2R activation, production and release of nitric oxide (NO) by endothelial cells, whereas increased concentration of AngII leads to vasoconstriction due to activation of smooth muscle AT1R, resulting in decreased adrenal blood flow  cortex that develops from the adrenogonadal primordium, is composed of two zones: the inner zone, referred to as the fetal zone (FZ) with high expression of steroidogenic enzymes and a smaller outer zone, called definitive zone (DZ) where expression of steroidogenic enzymes is lower . The FZ The adrenal cortex is a highly plastic organ, in which environmental stimuli are translated to hormonal responses that can involve extreme tissue remodeling. Example of this is the ZG expansion observed under a low salt diet, which stimulates the renin-angiotensin system to promote aldosterone biosynthesis . On the ACTH is the main hormone regulating the function of the zona fasciculata and zona reticularis and stimulating glucocorticoid biosynthesis; it also stimulates, to a lesser extent, aldosterone production by the ZG. In addition, ACTH when binding to its receptor MC2R in the adrenals also induces the adrenal production of factors affecting adrenal growth and its blood flow. Indeed, ACTH controls angiogenesis and vascularization in the adrenal gland by stimulating the intra-adrenal production of VEGF and the vaso-relaxant EETs. On the other hand, VEGF can act on adrenal cells by binding on VEGF receptors present on adrenocortical cells and stimulates aldosterone production. Vascularization and adrenal cortex development must be coordinated to ensure that adrenocortical cells have access to blood vessels as the adrenal growths.via the same pathway, suggesting that ACTH may coordinate vascularization, adrenocortical development and steroidogenesis in the adrenal gland.The vasculature of the HFA is established by the eighth week of gestation when the adrenal is supplied by arteries from the descending aorta, and the capillary sinusoids within the gland form a continuum with the systemic circulation. This stimulation is mediated by specific angiogenic factors like VEGF . ShifrenIn addition to AngII, extracellular potassium and ACTH, endothelin and VEGF have been shown to stimulate aldosterone production in a paracrine manner , 77. In In vitro studies in cultured human adrenocortical cells revealed that cytokines like IL-6 and ET-1, as well as NO produced by endothelial cells, are the main actors in this interaction , has been shown to induce endothelial dysfunction, inflammation, remodeling, stiffening and atherosclerosis –88. In aAdrenals with APA show increased nodulation and reduced vascularization in the peritumoral adrenal cortex, as well as ZG hyperplasia . In addiWnt4, Tcf3, Lef1, without affecting the canonical Wnt pathway nor PKA signaling. Rarα inactivation also reduced the expression of VEGF-A, while other angiogenesis factors such as VEGF-C and Hif1α were not affected. In contrast, the expression of components of the extracellular matrix like fibronectin 1, microfibrillar associated protein 2 and 5 (Mfap2 and Mfap5) and collagen 3α1 were increased. Altogether, these data highlight the important role of the interplay between the vascular and hormonal components in the adrenal cortex and suggest that alterations affecting this interplay, such as modifications of the extracellular matrix composition, may contribute to the disorganization of the adrenal cortex by modulating adrenocortical and vascular cell migration  contributes to the maintenance of normal adrenal cortex structure and cell proliferation in mice, by modulating non-canonical Wnt signaling, extracellular matrix composition and angiogenesis. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA . Indeed,igration .As observed in normal adrenals, it is expected that endothelin secreted by adrenal vessels and its signaling pathway in steroidogenic cells can stimulate aldosterone production and may have a role in its autonomous overproduction and by consequence contribute to the development of PA . Rossi evia MC2R may be involved, as MC2R was highly expressed in these same regions.Recently, we have investigated the relationship between different signaling pathways and components of the microenvironment in adrenals with APA. We have applied multiplex immunofluorescence and multispectral image analysis to investigate the colocalization of proteins involved in aldosterone (CYP11B2) and cortisol (CYP11B1/CYP17A1) biosynthesis, markers of Wnt/β-catenin (β-catenin) and ACTH/cAMP/PKA  signaling, as well as paracrine pathways of the tumor microenvironment  and vascularization (CD34) . Whether it was a benign or a malignant tumor, carriers of adrenocortical tumors showed higher circulating VEGF levels in comparison with healthy subjects , 102. InIn conclusion, the coordinated interaction between steroidogenic and endothelial cells plays a crucial role in adrenal development and function and allows adrenal cortex remodeling in response to different physiological stimuli, such as modifications of sodium diet or stress response. Key players in this interaction appear to be ACTH and VEGF, which cross-talk to regulate hormone biosynthesis and vessel growth Figure 1All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The laboratory of Dr. Maria-Christina Zennaro is supported through institutional funding from INSERM, by the Agence Nationale de la Recherche (ANR-18-CE93-0003-01) and the Fondation pour la Recherche Médicale (EQU201903007864).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Violence against healthcare workers (HCWs) has gained increasing attention in recent years, both because it is on the rise and because there is growing concern about these incidents, which are classified as sentinel events by the Italian Ministry of Health. Since little is known about the actual burden of this phenomenon, especially during the stressful COVID-19 vaccination campaign, we decided to explore the problem in our region.Between January and March 2022, in the 1.2 million-inhabitant Friuli Venezia Giulia region , we conducted an anonymous online survey to collected data on episodes of violence and their consequences for HCWs. Data from validated tools assessing characteristics of violent episodes and post-trauma impact were analyzed in conjunction with socio-demographic data of respondents.200 HCWs participated in the survey, most of whom were women (72%), worked as nurses (107) or doctors (71), and had a mean age of 47 years. More than half of them (59%) reported at least one episode of violence, mainly in the form of a verbal assault (64%); there were no differences between victims. In 72 cases, these incidents affected the HCW’s private life, mainly disturbing sleep or concentration (68%). Most HCWs stated that inadequate communication was a trigger for the violence (97%). Although 80% of HCWs would readily report any violent incident, to improve the situation they called for certainty of action against the perpetrator (87%), more organizational support (85%), standard procedures (75%) and self-defense courses (75%).Violence in COVID-19 vaccination campaign appears to be common and to affect both the personal and professional lives of HCWs. Improvements at the institutional and personal level could help to address this problem that affects the health workforce.• Given the growing public debate, violence in healthcare settings is an important issue that needs to be addressed in the coming years.• Assessing workplace violence and its associated risk factors will help focus on the strategies that can be usefully employed to prevent it in the future.


Head and neck squamous cell carcinoma (HNSCC) has long been one of the most prevalent cancers worldwide; even though treatments such as surgery, chemotherapy, radiotherapy and immunotherapy have been proven to benefit the patients and prolong their survival time, the overall five-year survival rate is still below 50%. Hence, the development of new therapies for better patient management is an urgent need. External stimuli-responsive therapies are emerging therapies with promising antitumor effects; therapies such as photodynamic (PDT) and photothermal therapies (PTT) have been tested clinically in late-stage HNSCC patients and have achieved promising outcomes, while the clinical translation of sonodynamic therapy (SDT), radiodynamic therapy (RDT), microwave dynamic/thermodynamic therapy, and magnetothermal/magnetodynamic therapy (MDT/MTT) still lag behind. In terms of preclinical studies, PDT and PTT are also the most extensively studied therapies. The designing of nanoparticles and combinatorial therapies of PDT and PTT can be referenced in designing other stimuli-responsive therapies in order to achieve better antitumor effects as well as less toxicity. In this review, we consolidate the advancements and limitations of various external stimuli-responsive therapies, as well as critically discuss the prospects of this type of therapies in HNSCC treatments. Head and neck squamous cell carcinoma (HNSCC), which accounts for approximately 90% of head and neck cancers, has long been one of the most prevalent cancers worldwide . AssociaNanotechnology provides us with various direct and indirect methods of treating cancer. For example, a nanodelivery system can carry anticancer drugs directly to the cancer lesion and reduce the blood drug concentration, thus minimizing the toxicity of anticancer drugs; nanomaterials that can be excited by a stimulator  can kill cancer cells directly through producing reactive oxygen species (ROS) or energy (radiation and heat) ; some naSeveral works have described the applications of nanotechnology in HNSCC, but a review going through all types of potent stimuli-responsive nanotherapies is still in urgent need ,10,11,12PDT has been improved greatly since 1898, when Oscar Raab first established the basic concept of photodynamic treatment . PDT invSome photosensitizers such as Foscan have already been approved for palliative treatment and have shown robust clinical benefits in HNSCC patients ,15. PhotPorphyrin sodium ,18, mTHPThe recent trend in preclinical photodynamic therapy development mainly lies in two fields; one is by modifying the biomaterials or combining them with other materials in order to improve their tumor affinity or to enhance the antitumor effect, and the other one is to modify the tumor microenvironment and supply oxygen for ROS generation.2O2, the H2O2 reacts with the CPPO, thus releasing energy and exciting the Ce6, and the hemoglobin works as an oxygen donor for both lactate catabolism and PDT. All four materials are assembled into nanoparticles made from U251 glioma cells for specialized delivery to the tumor 39], Pd  and Pt , and theEfforts have been made in improving the innate disadvantages of each type of PTT agent. In noble metal nanomaterial agents, it is challenging to deliver them specifically to the tumor tissue while ensuring efficient biodegradation and biosafety. Various tumor-targeting coatings have been fabricated on nanomaterials to facilitate the accumulation in tumor tissues and cells. Sun et al. coated gold nanorods with a cancer cell membrane (GNR@Mem), which showed preferable homotypic targeting to cancer cells in vitro . The in 3O4@Au/reduced graphene oxide nanostructures as the photo- and radiosensitizers 96], Ce , La 98]98], Eu ), transi3:Ce(3+)/DMSO nanoparticle and combined it with PpIX and achieved preferable antitumor effects in prostate cancer models [So far, there is no clinical application or study on radiodynamic therapy in HNSCC; in addition, preclinical study on RDT application in HNSCC cell lines is still lacking. Nanoparticles from previous studies on other types of cancer can be referenced to develop RDT designs for HNSCC treatment. The most basic design of the nanoparticles includes scintillating particles combined with photosensitizers; for example, Zou et al. synthesized the LaFr models . Novel rr models .2O2 catalysts such as MnO2 [To improve the accumulation of the radiosensitizers in the tumor tissue, the nanoparticles can be conjugated to a certain targeting moiety to facilitate specific delivery . Some no as MnO2  into theMicrowaves have long been utilized in clinical settings for tumor ablation, which is known as microwave thermal therapy. The mechanism of its antitumor effect is similar to that of photothermal therapy; while a temperature of 41 °C can cause vasodilation, thus increasing the blood perfusion to the tumor as well as causing heat shock response of cells, temperatures above 46 °C can lead to irreversible cell death . VariousAfter an extensive literature search, we failed to find any studies on HNSCC both clinically and preclinically. Nanoparticle designs for other types of cancer can be referenced and adapted for HNSCC treatment development. Here, we introduce some representative nanoparticle designs that showed great potential in other cell lines.2) nanoparticles that were co-decorated with mitochondrial-targeting molecules of triphenylphosphonium (TPP) and tumor cell-targeting peptide iRGD; the nanoparticle complex showed an ideal targeting effect and sufficient accumulation in tumor tissue, and thus achieved preferable antitumor effects in an H22 tumor model [2+-surplus alginate hydrogel, which demonstrated preferable microwave-thermal conversion and the immunostimulatory effect. Such a hydrogel also carries favorable biocompatibility, which gives it great potential in future clinical translation [Wu et al. synthesized the zeolitic imidazolate Frameworks-8 (ZIF-8) and coated it with bovine serum protein, and the BSA@ZIF-8 exhibited favorable microwave thermal conversion and demonstrated a preferable antitumor effect in H22 xenograft models . Chen etor model . A very nslation . This stMagnetothermal therapy is a hyperthermia therapy mediated by an alternating magnetic field (AMF) and magnetic nanoparticles. The alternating current magnetic fields activate the nanoparticles and produce heat via magnetic hysteresis losses or Néel relaxation . There iThough hyperthermia treatment has long been used for HNSCC treatment , magnetoIn future studies of magnetic therapies for HNSCC, colossal magneto-resistive materials can probably be attempted due to their high magnetic transition temperature, TC (≥360 K) . Magneto2 or H2O2 in the tumor microenvironment to generate cytotoxic hydroxyl radicals. Instead, it decomposes water and generates ROS with the assistance of chlorine ions [Electrodynamic therapy has a similar mechanism as other dynamic therapies; the main mechanism is the generation of reactive oxygen species (ROS) using platinum nanoparticles (PtNP) under the stimulation of an alternating electric field. The ROS subsequently triggers cell apoptosis and immune reactions . Unlike ine ions . Moreove2O2 in the tumor microenvironment, and the H2O2 is subsequently decomposed by the platinum nanospheres and generates O2 to facilitate the glucose consumption by GOx. The combination of GOx-mediated tumor starvation and EDT exhibited good antitumor effects both in vitro and in vivo [3O4 into PtNP to facilitate ROS generation as well as GSH depletion [So far, there has not been much research on EDT, and its clinical development is also preliminary. In terms of HNSCC, we did not find any preclinical or clinical studies on it even after an extensive literature search. Within all of the available research papers, BALB/c mice bearing 4T1 tumors are the most frequently studied animal model. Gu et al. tested the antitumor efficacy of PtNP in 4T1 tumor cells and achieved preferable antitumor effects both in vitro and in vivo , which i in vivo . Similar in vivo . Anotherepletion .So far, most of the studies on EDT have focused on modifying the tumor microenvironment; future studies can lay more emphasis on targeted delivery or combinatorial therapies. In addition, clinical translation is encouraged, since Pt has been indicated to possess lower cytotoxicity and stronger stability in the physiological environment .The recent development of various stimuli-responsive treatments and nanomaterials has attracted many researchers with different academic backgrounds. Some clinical studies have already indicated the potential and clinical efficacy of certain types of stimuli-responsive therapies such as photodynamic and photothermal therapies in head and neck squamous cell carcinoma treatment, while a large number of preclinical studies have provided us with various novel nanoparticle designs with better biocompatibility, better targeting effects, lower cytotoxicity and promising future clinical applications.Photodynamic treatment has been used clinically for quite a long time and has been extensively studied both clinically and preclinically. Hence, the research progress of photodynamic treatment is far ahead of the remaining types of stimuli-responsive treatments. Thus, the recent progress in photodynamic nanoparticle designs such as tumor microenvironment modification, targeted delivery, more favorable biodegradability, boosted photodynamic effects and external stimuli-free design can all be referenced and applied in other less extensively studied therapies such as sonodynamic treatment, radiodynamic treatment, magnetodynamic treatment, etc.Various preclinical studies especially on photodynamic and photothermal therapy have indicated that the stimuli-responsive therapies have shown a very good synergistic effect with chemotherapy, immunotherapy, and other types of stimuli-responsive therapy. Thus, combinatorial treatment should be paid more attention especially in those less extensively studied therapies such as sonodynamic, radiodynamic, magnetodynamic, electrodynamic and microwave dynamic therapy. Additionally, some agents with the characteristic of being excited by more than one type of external stimuli are natural candidates for combinatorial treatment.More translational studies are also required since the clinical studies lag far behind the preclinical studies; the synthesized nanoparticles are getting more complex and more multifunctional, making their preclinical results better. Though the newer generation of stimuli-responsive nanoparticles is more potent in preclinical research, manufacturing complexities are hindering its clinical translation. In order to facilitate future clinical translation, efficacy, ease of use, inexpensiveness and ease of synthesis should be paid more attention to. More prompt clinical trials are encouraged when the safety of the agent can be ensured and the therapeutic effect is proven to be superior to the current treatment regimen. Considerable room exists for the preclinical and clinical expansion of various stimuli-responsive treatments with nanotechnology innovations and therapeutic strategy improvements.