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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
In HF, excitation contraction coupling is impaired through three intracellular changes: (1) decreased expression and function of SERCA-2a; (2) increased calcium leak through ryanodine receptors; and (3) increased transport of calcium out of the cell through enhanced expression and function of the sodium-calcium exchanger. Together, these processes impair inotropy through depletion of intracellular calcium and reduced calcium-induced calcium release from the sarcoplasmic reticulum, and lusitropy should be impaired or decreased in heart failure due to slow removal of calcium from the cytosol after completion of an action potential-contraction cycle.11
Nitric Oxide and Myocardial Contraction: Experimental Studies
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Richard M. Grocott-Mason, Peter B. Anning, Malcolm J. Lewis, Ajay M. Shah
NO may also have an important role in preventing the characteristic diastolic dysfunction observed after recovery from an ischaemic insult. In isolated cat papillary muscles, SNP inhibited the profound delay in myocardial relaxation during recovery from hypoxia, without influencing peak developed tension, consistent with a selective effect on relaxation (Brodie et al., 1976). Similarly, in isolated rat cardiac myocytes, pretreatment with a cyclic GMP analogue abolished the abnormal relaxation which follows brief hypoxia-reoxygenation (Shah et al., 1995). A possible role of impaired NO in cardiac autonomic dysfunction remains speculative. An interesting recent report in humans with heart failure suggested that whilst NO attenuated the ‘systolic’ response to β-agonists, the lusitropic effects were preserved (Hare et al., 1995c).
Clinical features of mitral stenosis
Published in Neeraj Parakh, Ravi S. Math, Vivek Chaturvedi, Mitral Stenosis, 2018
LV diastolic filling characteristics (LV relaxation abnormality [lusitropy]/LV wall stiffness [LV hypertrophy]). Any impairment in LV relaxation in early diastole (negative lusitropy) compromising active LV suction (hampering early diastolic LV filling) as well as LV hypertrophy-related increase in LV stiffness (especially in mid- and late diastole) will result in an increase in mean LA pressure, to maintain the same forward stroke volume.
The current and future status of inotropes in heart failure management
Published in Expert Review of Cardiovascular Therapy, 2023
Angelos Arfaras-Melainis, Ioannis Ventoulis, Effie Polyzogopoulou, Antonios Boultadakis, John Parissis
Istaroxime operates on the cardiac myocyte through a dual mechanism: Firstly, by blocking the sarcolemmal sodium-potassium ATPase, and secondly, by activating the sarcoendoplasmic reticulum calcium adenosine triphosphatase isoform 2a (SERCA2a). The first leads to improved contractility by raising the levels of intracellular Ca2+, while the second leads to enhanced lusitropy by promoting the absorption of free Ca2+into the sarcoplasmic reticulum during diastole [63]. In HORIZON-HF (Hemodynamic, Echocardiographic and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent, in Patients Hospitalized with Worsening Heart Failure and a Reduced Left Ventricular Systolic Function), a double-blind phase II study, the use of istaroxime was associated with an improvement in the hemodynamic profile (decreased PCWP, increased mean arterial pressure), without causing myocardial damage/necrosis [32,64]. More recently in 2022, in the SEISMiC (The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock) trial, a phase IIa study in patients with pre-cardiogenic shock defined as stage B according to the classification by the Society for Cardiovascular Angiography and Interventions (SCAI), Metra et al reported that istaroxime improved blood pressure along with several echocardiographic parameters [33]. Consequently, istaroxime seems to emerge as a promising inotropic agent that is currently being further investigated for patients with HF.
Clinical pharmacology of cardiac cyclic AMP in human heart failure: too much or too little?
Published in Expert Review of Clinical Pharmacology, 2023
An equally central role is played by cAMP in cardiac relaxation (positive lusitropy). The importance of this sometimes gets diluted by the focus given on cAMP's actions toward positive inotropy. Nevertheless, cAMP is essential for cardiac relaxation, a process necessary for proper ventricular filling during diastole, which, in turn, is a critical determinant of cardiac function, i.e. of the force of the next contraction (based on the Frank–Starling law of normal cardiac operation) [25,26] (Figure 1). Additionally, proper diastolic function is important for cardiac muscle oxygenation and nourishment, as the coronary arteries can only deliver blood to the cardiac cells during diastole (compressed during systole/contraction) [252626, . PKA is again the main mediator of cAMP's effects in cardiac relaxation. PKA lowers the free intracellular [Ca2+] (removes Ca2+ from the cytosol) via SERCA2a activation in the SR membrane (by phosphorylating phospholamban) and Na+/K+-ATPase (NKA) activation in the plasma membrane (by phosphorylating phospholemman), which induces the Na+/Ca2+-exchanger (NCX) to remove Ca2+ out of the cardiomyocyte [17,19] (Figure 1). At the same time, PKA reduces the Ca2+ sensitivity of actomyosin filaments and increases their distensibility via phosphorylation of cardiac troponin I (cTnI), titin, and cardiac myosin-binding protein-C3 (MyBPC3) [27,28,29] (Figure 1).
Cardioprotective effects of Galium verum L. extract against myocardial ischemia-reperfusion injury
Published in Archives of Physiology and Biochemistry, 2020
Jovana Bradic, Nevena Jeremic, Anica Petkovic, Jovana Jeremic, Vladimir Zivkovic, Ivan Srejovic, Jasmina Sretenovic, Stevan Matic, Vladimir Jakovljevic, Marina Tomovic
Our results clearly show that cardiodynamic parameters in control conditions were substantially reduced during reperfusion compared to values before ischemia. We obtained depression of cardiac function and impaired inotropic and lusitropic properties of the heart, as well as disturbed coronary circulation and HR, thus confirming that I/R injury is related to myocardial tissue dysfunction. On the other hand, 4 weeks treatment with G. verum extract did not only preserve contractile power of the heart, but even improved it, as evidenced by increase in dp/dt max values at the end of reperfusion compared to the values before ischemia. Additionaly, administration of G. verum significantly restored lusitropic property of myocardium and led to the recovery of systolic and diastolic function in comparison to hearts in control conditions. Restoration of flow was noticed in first minutes of reperfusion and it was followed by a slow continuous drop over 30 min reperfusion period, so at the end of recovery period it returned to the values observed before ischemia. The similar dynamic during reperfusion was noticed in terms of contractility force, thus suggesting that vasculature dilated in accordance with the demands of myocardial contraction. Insignificantly altered HR in rats who received G. verum provided sufficient time for myocardium to contract strongly.