Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression

Røe, Åsmund T.; Ruud, Marianne; Espe, Emil Knut Stenersen; Manfra, Ornella; Longobardi, Stefano; Aronsen, Jan Magnus; Nordén, Einar Sjaastad; Husebye, Trygve; Kolstad, Terje R Selnes; Cataliotti, Alessandro; Christensen, Geir; Sejersted, Ole M.; Niederer, Steven; Andersen, Geir Øystein; Sjaastad, Ivar; Louch, William E.

doi:10.1093/cvr/cvy257

Cited by 27 publications

(32 citation statements)

References 38 publications

(89 reference statements)

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“…Its increased expression improves myocardial contractility and Ca 2+ handling [ 43 ]. Importantly, high mechanical stress is directly linked to SERCA2a down-regulation and slowing of relaxation [ 35 ]. In the post-MI model of the rat, regional diastolic dysfunction was linked to elevated wall stress adjacent to the infarction, resulting in down-regulation of SERCA, disrupted diastolic Ca 2+ handling, and local slowing of relaxation [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Its downregulation in heart failure leads to a loss of cardiac contractility whereas increased expression of SERCA2a improves contractility [ 34 ]. Down-regulation of SERCA2a after MI in rats was linked with diastolic dysfunction [ 35 ]. It was also assumed that a compensatory increase in NCX compensates for the reduced SERCA2a activity [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Goerg

Sommerfeld

Greiner

et al. 2021

IJMS

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The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Goerg

Sommerfeld

Greiner

et al. 2021

IJMS

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“…NCX activity was examined using the tail current elicited by repolarization following a 100 ms voltage step from −45 to 0 mV (illustrated in Online Figure IV). 6 Western Blotting and PCR Analyses Expression of KCNA5/K v 1.5 was examined by qPCR and Western blotting, as described in study by Røe et al 23 and Lipsett et al 24 , respectively.…”

Section: Patch-clamp Experimentsmentioning

confidence: 99%

Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes

Tazmini

Frisk

Laasmaa

et al. 2020

Biophysical Journal

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Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. OBJECTIVE: To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. METHODS AND RESULTS: Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K + ] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca 2+ overload and increased generation of both spontaneous Ca 2+ waves and delayed afterdepolarizations. However, similar Ca 2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na +-K + ATPase and Na +-Ca 2+ exchanger proteins within these structures, as reduction in Na + pump activity locally inhibited Ca 2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca 2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca 2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na + current, as they were rapidly blocked by tetrodotoxin. Na + current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K + current (I Kur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. CONCLUSIONS: Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology. VISUAL OVERVIEW: An online visual overview is available for this article.

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“…Velocity encoded tissue phase mapping (TPM) MRI enables measurement of myocardial velocities with high spatial and temporal resolution [ 5 ]. TPM data can also serve as a basis for deriving several characteristics that describes cardiac mechanical function on a regional level; such as strain [ 6 , 7 ], fiber shortening [ 8 ], strain rate [ 9 , 10 ], and work [ 11 ]. To derive these parameters, the velocity field must undergo either spatial differentiation (to get strain rate) or temporal integration (to get myocardial material point trajectories).…”

Section: Introductionmentioning

confidence: 99%

A 4D continuous representation of myocardial velocity fields from tissue phase mapping magnetic resonance imaging

et al. 2021

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Myocardial velocities carry important diagnostic information in a range of cardiac diseases, and play an important role in diagnosing and grading left ventricular diastolic dysfunction. Tissue Phase Mapping (TPM) Magnetic Resonance Imaging (MRI) enables discrete sampling of the myocardium’s underlying smooth and continuous velocity field. This paper presents a post-processing framework for constructing a spatially and temporally smooth and continuous representation of the myocardium’s velocity field from TPM data. In the proposed scheme, the velocity field is represented through either linear or cubic B-spline basis functions. The framework facilitates both interpolation and noise reducing approximation. As a proof-of-concept, the framework was evaluated using artificially noisy (i.e., synthetic) velocity fields created by adding different levels of noise to an original TPM data. The framework’s ability to restore the original velocity field was investigated using Bland-Altman statistics. Moreover, we calculated myocardial material point trajectories through temporal integration of the original and synthetic fields. The effect of noise reduction on the calculated trajectories was investigated by assessing the distance between the start and end position of material points after one complete cardiac cycle (end point error). We found that the Bland-Altman limits of agreement between the original and the synthetic velocity fields were reduced after application of the framework. Furthermore, the integrated trajectories exhibited consistently lower end point error. These results suggest that the proposed method generates a realistic continuous representation of myocardial velocity fields from noisy and discrete TPM data. Linear B-splines resulted in narrower limits of agreement between the original and synthetic fields, compared to Cubic B-splines. The end point errors were also consistently lower for Linear B-splines than for cubic. Linear B-splines therefore appear to be more suitable for TPM data.

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Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression

Cited by 27 publications

References 38 publications

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes

A 4D continuous representation of myocardial velocity fields from tissue phase mapping magnetic resonance imaging

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