Sacubitril/valsartan preserves regional cardiac function following myocardial infarction in rats.

Aims: Sacubitril/valsartan (Sac/Val) is used for treatment of heart failure. The effect of Sac/Val on regional dysfunction following myocardial infarction (MI) remains uncertain. This study aimed at understanding the effects of Sac/Val on regional function after MI.

Temporal expression and spatial distribution of the proteoglycan versican during cardiac fibrosis development.

Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated.

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.

Background: Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.

Methods: MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35-40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery.

CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor.

Background: Available evidence suggest that Ca/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.

Integrin α11β1 and syndecan-4 dual receptor ablation attenuate cardiac hypertrophy in the pressure overloaded heart.

Pathological myocardial hypertrophy in response to an increase in left ventricular (LV) afterload may ultimately lead to heart failure. Cell surface receptors bridge the interface between the cell and the extracellular matrix (ECM) in cardiac myocytes and cardiac fibroblasts and have been suggested to be important mediators of pathological myocardial hypertrophy. We identify for the first time that integrin α11 (α11) is preferentially upregulated among integrin β1 heterodimer-forming α-subunits in response to increased afterload induced by aortic banding (AB) in wild-type (WT) mice.

Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload.

Aims: Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin-angiotensin-aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF).

Methods And Results: Sprague-Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks.

Noninvasive stratification of postinfarction rats based on the degree of cardiac dysfunction using magnetic resonance imaging and echocardiography.

The myocardial infarction (MI) rat model plays a crucial role in modern cardiovascular research, but the inherent heterogeneity of this model represents a challenge. We sought to identify subgroups among the post-MI rats and establish simple noninvasive stratification protocols for such subgroups. Six weeks after induction of MI, 49 rats underwent noninvasive examinations using magnetic resonance imaging (MRI) and echocardiography.

Syndecan-4 is a key determinant of collagen cross-linking and passive myocardial stiffness in the pressure-overloaded heart.

Aims: Diastolic dysfunction is central to the development of heart failure. To date, there is no effective treatment and only limited understanding of its molecular basis. Recently, we showed that the transmembrane proteoglycan syndecan-4 increases in the left ventricle after pressure overload in mice and man, and that syndecan-4 via calcineurin/nuclear factor of activated T-cells (NFAT) promotes myofibroblast differentiation and collagen production upon mechanical stress.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan-4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure-overloaded heart.

Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention.

Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway.

Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload.

Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload.

Aims: Left ventricular (LV) pressure overload leads to myocardial remodelling and reduced cardiac function. Both cardioprotective and deleterious effects have been attributed to SMAD2/3 (SMAD, small mothers against decapentaplegic) signalling, but the role of these important molecules in pressure overload remains unclear. The aim of this study was to examine the effects of SMAD2 inhibition on cardiac function and remodelling in mice subjected to aortic banding (AB), using a small molecule inhibitor (SM16) of SMAD2 signalling.

Collagen isoform shift during the early phase of reverse left ventricular remodelling after relief of pressure overload.

Aims: Aortic stenosis induces pressure overload and myocardial remodelling with concentric hypertrophy and alterations in extracellular matrix (ECM). Aortic valve replacement leads to reverse remodelling, a process of which knowledge is scarce. The aims of the present study were to examine alterations in myocardial gene expression and subsequently identify molecular alterations important for the early phase of reverse remodelling.

Training effects on skeletal muscle calcium handling in human chronic heart failure.

Purpose: Patients with chronic heart failure (CHF) typically complain about skeletal muscle fatigue. In rat experiments, reduced intracellular calcium release seems to be related to fatigue development in normal skeletal muscle but not in muscle from rats with CHF. We therefore hypothesize that training may not improve intracellular calcium cycling to the same extent in muscles from patients with CHF compared with healthy controls (HC).