L. De Windt

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation.

Abstract An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 °C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1±1.7 ml min–1, 83±5 mm Hg and 6283±552 mm Hg s–1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6±1.8 ml min–1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.

A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3′-untranslated region (3′-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3′-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.

Pre-eclampsia : an important risk factor for asymptomatic heart failure

Pre‐eclampsia (PE) is associated with both postpartum structural asymptomatic heart disease (i.e. heart failure Stage B (HF‐B)) and conventional cardiovascular (CV) risk factors. We aimed to evaluate the extent to which PE, adjusted for conventional CV risk factors, is associated independently with asymptomatic cardiac abnormalities postpartum.

Cardiac remodeling and pre‐eclampsia: an overview of microRNA expression patterns

Pre‐eclampsia (PE) is strongly associated with heart failure (HF) later in life. During PE pregnancy, the left ventricle undergoes concentric remodeling which often persists after delivery. This aberrant remodeling can induce a molecular signature that can be evaluated in terms of microRNAs (miRNAs) and which may help to explain the associated increased risk of HF. For this review, we performed a literature search of PubMed (National Center for Biotechnology Information), identifying studies on miRNA expression in concentric remodeling and on miRNA expression in PE. The miRNA data were stratified based on origin (isolated from humans or animals and from tissue or the circulation) and both datasets compared in order to generate a list of miRNA expression patterns in concentric remodeling and in PE. The nine miRNAs identified in both concentric remodeling and PE‐complicated pregnancy were: miR‐1, miR‐18, miR‐21, miR‐29b, miR‐30, miR‐125b, miR‐181b, miR‐195 and miR‐499‐5p. We found five of these miRNAs (miR‐18, miR‐21, miR‐125b, miR‐195 and miR‐499‐5p) to be upregulated in both PE pregnancy and cardiac remodeling and two (miR‐1 and miR‐30) to be downregulated in both; the remaining two miRNAs (miR‐29b and miR‐181b) showed upregulation during PE but downregulation in cardiac remodeling. This innovative approach may be a step towards finding relevant biomarkers for complicated pregnancy and elucidating their relationship with remote cardiovascular disease. Copyright