Early detection of cardiac involvement in thalassemia: From bench to bedside perspective

Myocardial siderosis is known as the major cause of death in thalassemia major(TM) patients since it can lead to iron overload cardiomyopathy.Although this condition can be prevented if timely effective intensive chelation is given to patients,the mortality rate of iron overload cardiomyopathy still remains high due to late detection of this condition.Various direct and indirect methods of iron assessment,including serum ferritin level,echocardiogram,non-transferrin-bound iron,cardiac magnetic resonance T2*,heart rate variability,and liver biopsy and myocardial biopsy,have been proposed for early detection of cardiac iron overload in TM patients.However,controversial evidence and limitations of their use in clinical practice exist.In this review article,all of these iron assessment methods that have been proposed or used to directly or indirectly determine the cardiac iron status in TM reported from both basic and clinical studies are comprehensively summarized and presented.Since there has been growing evidence in the past decades that cardiac magnetic resonance imaging as well as cardiac autonomic status known as the heart rate variability can provide early detection of cardiac involvement in TM patients,these two methods are also presented and discussed.The existing controversy regarding the assessment of cardiac involvement in thalassemia is also discussed.

Calcium channels and iron uptake into the heart

Iron overload can lead to iron deposits in many tissues,particularly in the heart.It has also been shown to be associated with elevated oxidative stress in tissues.Elevated cardiac iron deposits can lead to iron overload cardiomyopathy,a condition which provokes mortality due to heart failure in iron-overloaded patients.Currently,the mechanism of iron uptake into cardiomyocytes is still not clearly understood.Growing evidence suggests L-type Ca2+channels(LTCCs)as a possible pathway for ferrous iron(Fe2+)uptake into cardiomyocytes under iron overload conditions.Nevertheless,controversy still exists since some findings on pharmacological interventions and those using different cell types do not support LTCC’s role as a portal for iron uptake in cardiac cells.Recently,T-type Ca2+channels (TTCC)have been shown to play an important role in the diseased heart.Although TTCC and iron uptake in cardiomyocytes has not been investigated greatly,a recent finding indicated that TTCC could be an important portal in thalassemic hearts.In this review,comprehensive findings collected from previous studies as well as a discussion of the controversy regarding iron uptake mechanisms into cardiomyocytes via calcium channels are presented with the hope that understanding the cellular iron uptake mechanism in cardiomyocytes will lead to improved treatment and prevention strategies,particularly in iron-overloaded patients.

Phosphodiesterase-3 inhibitor （cilostazol） attenuates oxidative stress-induced mitochondrial dysfunction in the heart

BackgroundCilostazol 是是的 3 phosphodiesterase 禁止者以前表明了阻止 tachyarrhythmia 的出现并且改进 defibrillation 功效的一种类型。然而，为这有益的效果的机制仍然是不清楚的。因为心脏的线粒体被显示了玩，在致命的心脏的心律不齐和那个氧化压力的一个关键角色是到心律不齐产生的主要贡献者之一，我们在严重氧化 stress.MethodsMitochondria 下面在心脏的线粒体上测试了 cilostazol 的效果从老鼠心被孤立并且与 H 对待 2导致氧化应力的 O 2。在各种各样的集中， Cilostazol 被用来学习它的保护的效果。药理学干预，包括一个 mitochondrial 渗透转变毛孔(mPTP ) blocker， cyclosporine A (CsA ) ，和一条内部膜阴离子隧道(IMAC ) blocker， 4 ′； -chlorodiazepam (CDP ) ，被用来在心脏的线粒体上调查 cilostazol 的机械学的角色。心脏的 mitochondrial 当当由阻止 mitochondrial 去极暴露了到氧化应力时，心脏的 mitochondrial function.ResultsCilostazol 的指示物保存了心脏的 mitochondrial 功能，反应的氧种类( ROS )生产，胀大的 mitochondrial 膜潜力变化和 mitochondrial 被决定， mitochondrial 胀大，并且减少 ROS production.ConclusionsOur 调查结果建议 cilostazol 的效果以前报导了的那 cardioprotective 能由于它的

PPARγ activator,rosiglitazone:Is it beneficial or harmful to the cardiovascular system?

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with typeⅡdiabetes.Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity.Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction,inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation,and the protection of myocardial injury during ischemic/reperfusion in different animal models.Previous clinical studies in typeⅡdiabetes patients demonstrated that rosiglitazone played an important role in protectingagainst arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system.Despite these benefits,inconsistent findings have been reported,and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system,including increased risk of acute myocardial infarction,heart failure and chronic heart failure.As a result,rosiglitazone has been recently withdrawn from EU countries.Nevertheless,the effect of rosiglitazone on ischemic heart disease has not yet been firmly established.Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.

Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury:Cumulative evidence for future cardioprotective strategies

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction(MI)and myocardial ischemia/reperfusion(MI/R)injury.Due to the limited regenerative ability of cardiomyocytes,understanding the mechanisms of cardiomyocyte death is necessary.Pyroptosis,one of the regulated programmed cell death pathways,has recently been shown to play important roles in MI and MI/R injury.Pyroptosis is activated by damage-associated molecular patterns(DAMPs)that are released from damaged myocardial cells and activate the formation of an apoptosisassociated speck-like protein containing a CARD(ASC)interacting with NACHT,LRR,and PYD domains-containing protein 3(NLRP3),resulting in caspase-1 cleavage which promotes the activation of Gasdermin D(GSDMD).This pathway is known as the canonical pathway.GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11.Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury.Although the effects of MI or MI/R injury on pyroptosis have previously been discussed,knowledge concerning the roles of GSDMD in these settings remains limited.In this review,the evidence from in vitro,in vivo,and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed.Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease.