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Pathophysiology of Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jacob Cao, John O'Sullivan, Sean Lal
Excitation contraction coupling refers to the coordinated process that starts when the action potential arrives at the sarcolemmal membrane and ends with sarcomere contraction and relaxation (Figure 3.4). Calcium plays a pivotal role in this entire process. Upon activation of the voltage-gated L-type calcium channels on the T tubules by the action potential, there is an initial small inward current of calcium. This small current acts on the closely apposed ryanodine receptors 2 and triggers a large release of calcium from the sarcoplasmic reticulum (calcium-induced calcium release). The cytosolic calcium subsequently binds to the cardiac troponin C. This induces conformational changes of the contractile proteins, leading to cross-bridge formation and sarcomeric contraction. The peak cytosolic calcium concentration is a major determinant of contractility. Relaxation occurs when the calcium is transported from the cytosol to either the sarcoplasmic reticulum via the SERCA-2a transporter (major mechanism) or out of the cells via the sodium-calcium exchanger (minor mechanism).
The heart
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Unlike skeletal muscle, whose only source of calcium is the sarcoplasmic reticulum, cardiac muscle also obtains calcium from the T tubules, which are filled with extracellular fluid. This calcium, which enters the myocardial cells through L-type Ca++ channels, binds to calcium receptors on the external surface of the sarcoplasmic reticulum. Receptor binding then stimulates the release of calcium from the sarcoplasmic reticulum. This mechanism is referred to as calcium-induced calcium release. Although most of the calcium utilized in the contractile process is obtained from the sarcoplasmic reticulum (90%), the release is dependent upon the movement of extracellular calcium into the muscle cells.
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
The most important source of activator calcium in cardiac muscle remains its release from the sarcoplasmic reticulum. Calcium, however, also enters from the extracellular space during the plateau phase of the action potential. This calcium entry provides the stimulus that induces calcium release from the sarcoplasmic reticulum (calcium-induced calcium release). The result is that tension generated in cardiac, but not in skeletal, muscle is profoundly influenced both by extracellular calcium levels and factors that affect the magnitude of the inward calcium current. This is of practical value in two key clinical situations: in heart failure where digoxin is used to increase cardiac contractility (by increasing the intracellular calcium concentration) and in hyperkalaemia where calcium gluconate is used to stabilize the myocardium.
Characterization of a novel stimulus-induced glial calcium wave in Drosophila larval peripheral segmental nerves and its role in PKG-modulated thermoprotection
Published in Journal of Neurogenetics, 2021
Jennifer L. Krill, Ken Dawson-Scully
Whether this propagation extended intracellularly to neighboring glial cells was not resolved in this current study. It is important to note that observations did show glial wave propagation into neighboring glial processes, however, classification of intercellular or intracellular propagation is still unknown. PKG activates KATP channels on the mitochondrial membrane (Costa et al., 2006), disrupting K+ homeostasis along the membrane and triggering membrane depolarization. This would essentially shut down mitochondrial function and prevent calcium uptake by the mitochondria, leaving the ER to buffer cytosolic calcium. The source of calcium-induced calcium release within PKG activation could be entirely reliant of the ER as PKG not only activates KATP channels on the mitochondrial membrane, but also activates ryanodine receptors on the membrane of the ER (Lu & Hawkins, 2002). Activation of ryanodine receptors triggers the release of calcium from the ER store. Reuptake via SERCA channels is not inhibited by PKG, allowing reuptake back into the ER. Shutting down mitochondrial function with the loss of K+ homeostasis would prevent ATP synthesis and leave only ER calcium signaling in the glial wave. This combination of these events coordinated through PKG activity could underlie the mechanism by which animals with high PKG activity shut down their function early during an acute stressor.
A special case of hypertrophic cardiomyopathy with a differential diagnosis of isolated cardiac amyloidosis or junctophilin type 2 associated cardiomyopathy
Published in Acta Clinica Belgica, 2021
Sévérine De Bruijn, Xavier Galloo, Gilles De Keulenaer, Edgard A. Prihadi, Christiane Brands, Mark Helbert
Unfortunately, our patient refused an endomyocardial biopsy. Genetic analysis was performed and revealed no known mutations in the genes coding for amyloid precursor proteins. Hence, we conclude that clinical circumstances and imaging results are most compatible with wtATTR. Interestingly, genetic testing did show a (previously undescribed) variant of yet another gene known to result in cardiac hypertrophy and heart failure, namely the JPH2 gene. Junctophilin type 2 protein is a cardio-specific member of the junctophilins, which is a family of junctional-membrane-complex proteins that play an important role in the physical approximation of a plasmalemmal calcium channel with a sarcoplasmic reticulum ryanodine receptor, which is necessary for calcium-induced calcium release. Defective junctophilin-2 and disrupted calcium signalling are now being investigated as a pathogenic mechanism for HCM [3,36]. The clinical significance of the variant in this case report is however unclear. The suggestion of further genetic analysis on his family members was rejected. To our knowledge, only one other case report describes the coexistence of amyloidosis and HCM. That patient suffered however of AL amyloidosis, proven by a renal biopsy, and genetic typing resulted positive for a double heterozygous mutation for MYH7 gene (suggesting HCM) and for MYBPC3 (a novel mutation).
A fatal ranolazine overdose after an intentional ingestion
Published in Clinical Toxicology, 2020
Robert Goodnough, Susan Kim-Katz, Adina Badea, Kara L. Lynch, L. Emily Cotter, Craig G. Smollin
Ranolazine exhibits 62–65% protein binding, p-glycoprotein transport, a volume of distribution (Vd) of 40.4–48.6 L, and CYP3A4 and CYP2D6 metabolism [2]. Polydrug p-glycoprotein interaction likely contributed to ranolazine toxicity. Ranolazine inhibits the delayed cardiac Na+ current, which persists past the peak Na+-current of the action potential [3]. Intracellular sodium from the delayed Na+-current exchanges for Ca2+ via a Na+/Ca2+ antiporter resulting in calcium-induced calcium release from the sarcoplasmic reticulum [3]. By inhibiting the delayed Na+-current and subsequent intracellular myocyte Ca2+-loading, Ranolazine essentially acts as an indirect calcium channel blocker. In contrast, peak Na+-channel blockers cause QRS prolongation and arrhythmogenic potential (not present in this case).