Paediatric dilated cardiomyopathy with and without endocardial fibroelastosis – a pathological analysis of 89 explants

Heart failure due to dilated cardiomyopathy is a major indication for paediatric cardiac transplantation. Endocardial fibroelastosis is a recognised pathological finding of unknown prognostic significance in paediatric dilated cardiomyopathy. To evaluate the nature of the association between left ventricular endocardial fibroelastosis and paediatric dilated cardiomyopathy, we reviewed surgical pathology reports of dilated cardiomyopathy explants (1986–2016) in order to characterise the pathological findings and to compare and contrast their frequency among four age groups: less than 1 year; 1–5 years; 6–10 years; and greater than 11 years. The 89 explants (47 males and 42 females) were all characterised by increased weight and left ventricular chamber dilatation without increased wall thickness. Ninety-five per cent of the specimens in the two youngest subsets had left ventricular endocardial fibroelastosis. Compared to the oldest age group, recipients aged 1–5 years had a 6-fold increase and those younger than 1 year a 19-fold increase in the odds of observing left ventricular endocardial fibroelastosis. Explants with and without endocardial fibroelastosis were otherwise phenotypically similar. In paediatric dilated cardiomyopathy endocardial fibroelastosis is a very common pathological finding, especially in infants and young children. We propose that the descriptive, clinico-pathological designation “Dilated Cardiomyopathy with Endocardial Fibroelastosis” should be adopted to facilitate future investigation into the potential prognostic/therapeutic significance of left ventricular endocardial fibroelastosis.

Surgical Treatment of Ischemic Dilative Cardiomyopathy by Ventricular Restoration

Patients with symptomatic post-ischemic dilative myocardiopathy of the left ventricle require, in selected cases, an operation to reshape and reduce the volume of the left ventricular chamber, in addition to surgical myocardial revascularization and mitral valve repair, with the aim of prolonging survival, improving the quality of life and minimizing the need for re-hospitalizations related to recurrent heart failure. This procedure is called surgical ventricular restoration (SVR), and is a useful tool for the treatment of heart failure patients as an alternative to heart transplant. This article provides an overview of surgical ventricular restoration for the treatment of dilative ischemic myocardiopathy. It illustrates several surgical options, describes the operative details, and discusses the correct indications for the procedure. Finally, an interesting protocol for one-step cell therapy during SVR is proposed, as an innovative treatment for heart failure patients.

Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice

Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload. Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.

Loss of Endogenously Cycling Adult Cardiomyocytes Worsens Myocardial Function

Rationale: Endogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle. Objective: We created and validated a new transgenic mouse, αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted αDKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), αDKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI. Methods and Results: A tandem αDKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The αDKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, αDKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre-treated αDKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 {plus minus} 0.5 vs. 3.3 {plus minus} 0.3 CMs per ten-micron section, N = 8-9 mice per group, n = 16-24 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was ~9 to 1 (5.2 {plus minus} 0.4 single vs. 0.6 {plus minus} 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in αDKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls. Conclusions: Although scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

Ablation of endogenously cycling adult cardiomyocytes worsens myocardial function after injury

RationaleEndogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle.ObjectiveWe created and validated a new transgenic mouse, αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted αDKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), αDKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI.Methods and ResultsA tandem αDKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The αDKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, αDKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre- treated αDKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 ± 0.5 vs. 3.3 ± 0.3 CMs per ten-micron section, N = 8 mice, n = 16 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was ∼9 to 1 (5.2 ± 0.4 single vs. 0.6 ± 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in αDKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls.ConclusionsAlthough scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

Abstract 224: A Deep Learning Approach to Left-Ventricular Chamber Quantification for Fully Automated Three Dimensional Strain Analysis in Cardiotoxicity

This study investigated MRI and semantic segmentation-based deep-learning (SSDL) automation for left-ventricular chamber quantifications (LVCQ) and low longitudinal strain (LLS) determination, thus eliminating user-bias by providing an automated tool to detect cardiotoxicity (CT) in breast cancer patients treated with antineoplastic agents. Displacement Encoding with Stimulated Echoes-based (DENSE) myocardial images from 26 patients were analyzed with the tool’s Convolution Neural Network with underlying Resnet-50 architecture. Quantifications based on the SSDL tool’s output were for LV end-diastolic diameter (LVEDD), ejection fraction (LVEF), and mass (LVM) (see figure for phase sequence). LLS was analyzed with Radial Point Interpolation Method (RPIM) with DENSE phase-based displacements. LVCQs were validated by comparison to measurements obtained with an existing semi-automated vendor tool (VT) and strains by 2 independent users employing Bland-Altman analysis (BAA) and interclass correlation coefficients estimated with Cronbach’s Alpha (C-Alpha) index. F1 score for classification accuracy was 0.92. LVCQs determined by SSDL and VT were 4.6 ± 0.5 vs 4.6 ± 0.7 cm (C-Alpha = 0.93 and BAA = 0.5 ± 0.5 cm) for LVEDD, 58 ± 5 vs 58 ± 6 % (0.90, 1 ± 5%) for LVEF, 119 ± 17 vs 121 ± 14 g (0.93, 5 ± 8 g) for LV mass, while LLS was 14 ± 4 vs 14 ± 3 % (0.86, 0.2 ± 6%). Hence, equivalent LV dimensions, mass and strains measured by VT and DENSE imaging validate our unique automated analytic tool. Longitudinal strains in patients can then be analyzed without user bias to detect abnormalities for the indication of cardiotoxicity and the need for therapeutic intervention even if LVEF is not affected.