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Implantable Device Therapy in Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Maxwell Eyram Afari, Lana Tsao
Cardiac contractility modulation (CCM), shown in Figure 6.2d, applies non-excitatory electrical signals to the cardiac tissue during the absolute refractory period, when the tissue cannot be activated.18 It is similar to a pacemaker system, consisting of a generator system connected to three leads (one atrial lead and two RV leads; Figure 6.2d). After delivery of high voltage (≈7.5 V), atrial-sensed biphasic impulse is sent to the RV septum which triggers the release of calcium in the sarcoplasmic reticulum. Calcium release is important in the cardiac excitation–contraction coupling, ultimately improving contractile performance without extra systolic contractions. Fundamentally, it differs from the pacemaker by the fact that it modulates contraction instead of the rhythm.
Optical Cardiovascular Imaging
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Crystal M. Ripplinger, Guy Salama, Igor R. Efimov
Calcium cycling is the most important component of cardiac excitation-contraction coupling. Normally, depolarization triggers intracellular Ca2+ ([Ca2+]i) transients but in pathological conditions, abnormalities in [Ca2+]i handling may activate Ca2+ dependent currents that influence the time course of the AP and trigger a spontaneous membrane depolarization (83,84). Abnormalities in [Ca2+]i handling have been implicated as the underlying mechanism in a number of pathologies that promote arrhythmias such as ischemia-reperfusion arrhythmias, the generation of early and delayed afterdepolarizations, and torsades de pointes. [Ca2+]i overload has been implicated in triggering electromechanical alternans and in increasing the steepness of APD restitution curves, which are both associated with the promotion of arrhythmias. Thus, one cannot overstate the importance of simultaneous measurements of APs and [Ca2+]i transients in intact hearts to address fundamental questions regarding the spatio-temporal relationship of transmembrane potential and [Ca2+]i and their interplay in arrhythmias.
Cardiac Performance During Diabetes
Published in Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla, Heart Dysfunction in Diabetes, 2019
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla
The alteration in cardiac performance during diabetes is dependent upon the duration of diabetes. Miller41 observed a depression in systolic pressure development, cardiac output, and aortic output of the isolated perfused working heart from diabetic rats as early as 3 days after the induction of diabetes with an injection of alloxan. This impairment in cardiac performance could be normalized by including insulin in the perfusate or elevating perfusate glucose concentrations substantially. Thus, it was concluded that the defect in cardiac function was due to an inability of the acutely diabetic rat heart to use glucose.41 This is not the case in the chronically diabetic animal. The defects in cardiac performance in rats made diabetic for several weeks (identified in Tables 1 and 2) are corrected to some extent38,43,44 by altering glucose delivery to the heart, but these hearts still exhibit significant functional depression in comparison to controls.38,39,42 Thus, the defect in cardiac performance observed in chronically diabetic rats is not primarily due to an inability to utilize perfusate glucose. Instead, intrinsic defects in the cardiac excitation-contraction coupling process have been suggested to cause the functional impairment.47–49 Approximately 1 month of diabetes is necessary before contractile deficiencies can be observed in hearts from chemically induced diabetic rats.39,42 In other studies the duration of diabetes is required to be 3 months before cardiac dysfunction was apparent in the chemically induced diabetic rabbit.46b Although no direct evidence is available, biochemical results strongly suggest cardiac function is depressed at 1 month of age in spontaneously diabetic BB/Worcester rats.50
Improving mitochondrial function in preclinical models of heart failure: therapeutic targets for future clinical therapies?
Published in Expert Opinion on Therapeutic Targets, 2023
Anna Gorący, Jakub Rosik, Joanna Szostak, Bartosz Szostak, Szymon Retfiński, Filip Machaj, Andrzej Pawlik
Heart failure is associated with oxidative stress and inflammation [34]. However, the association between oxidative stress and heart disease is still not completely clear [35]. Oxidative stress occurs when the balance between ROS generation and the antioxidant system is impaired [28]. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an indicator of oxidative stress in the heart and lungs [35]. It is also responsible for the adjustment of cardiac excitation-contraction coupling (ECC) and plays an important role in apoptotic signaling and remodeling [36]. The research shows that increased activation of CaMKII is observed in various heart illnesses [35] and is activated by H2O2 through oxidation [28]. This process leads to increased mitochondrial permeability, myocardial necrosis, and HF [37].
Diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients
Published in Expert Review of Hematology, 2018
Natthaphat Siri-Angkul, Siriporn C Chattipakorn, Nipon Chattipakorn
Gene therapy for curative treatment of thalassemia and novel pharmacological interventions to improve erythropoiesis, which are beyond the scope of this review, are still in their early stages, and their effects on iron overload cardiomyopathy remain to be assessed. Therefore, pathophysiology-oriented management of cardiac complications in TDT patients still merits further research. Biomedical science is continually constructing a firm base upon which future medical advances will be built, as could be illustrated by the ongoing attempts to find the pathways for cardiac iron entry and the detailed mechanisms of subsequent cellular iron mishandling. Regarding this issue, several interesting molecular players (for instance, L-type calcium channel, T-type calcium channel, and Lcn2) have been identified, but the relative importance of their roles is yet to be defined. Given the vital role of calcium ions in cardiac excitation–contraction coupling, further electrophysiological studies regarding the interference in the calcium current due to iron permeation through sarcolemmal L-type and T-type calcium channels may provide insight into iron-induced arrhythmogenesis. Even more limited are the studies focusing on the cardiac effects of Lcn2, which has been recently shown to be a pro-inflammatory, pro-apoptotic, iron-binding protein. Moreover, in an intermediate point on the scale linking the molecular and cellular views, the effects of iron overload on organellar (endoplasmic reticulum and mitochondria) functions are also not fully determined. These are only a few of the many unanswered fundamental questions that may eventually lead to improved diagnosis and treatment of cardiac siderosis in TDT patients.
Cardiac adenovirus-associated viral Presenilin 1 gene delivery protects the left ventricular function of the heart via regulating RyR2 function in post-ischaemic heart failure
Published in Journal of Drug Targeting, 2018
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yongji Yang, Changhai Lei, Shi Hu
In our current study, ischaemia damage resulted in a significant downregulation of PSEN1 gene expression. Exogenously overexpressed PSEN1 during sI/R elevated PSEN1 expression and restored RyR2 protein levels, suggesting that PSEN1 was involved in the degradation process of impaired RyR2 [35]. We therefore undertook this study to address whether PSEN1 gene addition might reverse the ventricular contractile dysfunction in failing myocardium. We used an AAV9 vector driving expression of the PSEN1 cDNA under control of a cardiac promoter to achieve long-term expression of PSEN1 in targeted LV regions [36]. Using a post-infarct HF model in the rat, our data provide the evidence that upregulation of PSEN1 protein via AAV-mediated myocardial PSEN1 gene delivery in failing myocardium can rescue contractile dysfunction both in vitro and in vivo. For the first time, to the best of our knowledge, our results show that AAV-PSEN1 treatment normalised dysfunctional intracellular Ca2+ handling, reversed foetal gene expression associated with HF, and restored Ca2+ handling in failing myocardium. All these results strongly support the hypothesis that Ca2+ signalling abnormalities, cardiac dysfunction and PSEN1 are key factors in the regulation of cardiac excitation-contraction coupling and HF. However, at this stage, we are not sure if its therapeutic effect is based on its rescue of RyR2 levels in sI/R or if it has other mechanisms by which it participates in the post-translational modification of RyR2. It will be important to examine the long-term effects of HF rescue. Given the urgency that exists in combating heart failure, our work demonstrates long-term therapeutic efficacy of AAV9-PSEN1 gene therapy delivered by a clinically relevant approach in a preclinical HF model.