Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed “responders”). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown. Methods: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders. Results: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions. Conclusions: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.

Myocyte hypertrophy antecedent to heart failure involves changes in global gene expression, although the preceding mechanisms to coordinate DNA accessibility on a genomic scale are unknown. Chromatin-associated proteins alter chromatin structure by changing their association with DNA, thereby altering the gene expression profile. Little is known about the global changes in chromatin subproteomes that accompany heart failure, and the mechanisms by which these proteins alter chromatin structure. The present study tests the fundamental hypothesis that cardiac growth and plasticity in the setting of disease recapitulates conserved developmental chromatin remodeling events. We used quantitative proteomics to identify chromatin-associated proteins extracted via detergent and to quantify changes in their abundance during disease. Our study identified 321 proteins in this subproteome, demonstrating it to have modest conservation (37%) with that revealed using strong acid. Of these proteins, 176 exhibited altered expression during cardiac hypertrophy and failure; we conducted extensive functional characterization of one of these proteins, Nucleolin. Morpholino-based knockdown of nucleolin nearly abolished protein expression but surprisingly had little impact on gross morphological development. However, hearts of fish lacking Nucleolin displayed severe developmental impairment, abnormal chamber patterning and functional deficits, ostensibly due to defects in cardiac looping and myocyte differentiation. The mechanisms underlying these defects involve perturbed bone morphogenetic protein 4 expression, decreased rRNA transcription, and a shift to more heterochromatic chromatin. This study reports the quantitative analysis of a new chromatin subproteome in the normal and diseased mouse heart. Validation studies in the complementary model system of zebrafish examine the role of Nucleolin to orchestrate genomic reprogramming events shared between development and disease.

Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes–induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.

This new edition of Sarah Franklin’s classic monograph on the development of in vitro fertilisation (IVF) includes two entirely new chapters reflecting on the relevance of the book’s findings in the context of the past two decades and providing a ‘state-of-the-art’ review of the field today. Over the past 25 years, both the assisted conception industry and the academic field of reproductive studies have grown enormously. IVF, in particular, is belatedly becoming recognised as one of the most influential technologies of the twentieth and twenty-first centuries, with a far-reaching set of implications that have to date been underestimated, understudied and under-reported. This pioneering text was the first to explore the emergence of commercial IVF in the United Kingdom, where the technique was originally developed. During the 1980s, the British Parliament devised a unique system of comprehensive national regulation of assisted reproduction amidst fractious public and media debate over IVF and embryo research. Franklin chronicles these developments and explores their significance in relation to classic anthropological debates about the meanings of kinship, gender and the 'biological facts' of parenthood. Drawing on extensive personal interviews with women and couples undergoing IVF, as well as ethnographic fieldword in early IVF clinics, the book explores the unique demands of the IVF technique. In richly detailed chapters, it documents the ‘topsy-turvy’ world of IVF, and how the experience of undergoing IVF changes its users in ways they had not anticipated. Franklin argues that such experiences reveal a crucial feature of translational biomedical procedures more widely – namely, that these are ‘hope technologies’ that paradoxically generate new uncertainties and risks in the very space of their supposed resolution. The final chapter closely engages with the ‘hope technology’ concept, as well as the idea of ‘having to try’ and uses these frames to link contemporary reproductive studies to core sociological and anthropological arguments about economy, society and technology. In the context of rapid fertility decline and huge growth in the fertility industry, this volume is even more relevant today than when it was first published at the dawn of what Franklin calls the era of 'iFertility'. Embodied Progress is an essential read for all social science academics and students with an interested in the burgeoning new field of reproductive studies. It is also a valuable resource for practitioners working in the fields of reproductive health, biomedicine and policy.