Harnessing the power of dividing cardiomyocytes

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Recently, our group demonstrated that neonatal mammalian hearts have a remarkable regenerative potential in the first few days after birth. Although adult mammals lack this regenerative potential, it is now clear that there is measurable cardiomyocyte turnover that occurs in the adult mammalian heart. In both neonatal and adult mammals, proliferation of pre-existing cardiomyocytes appears to be the underlying mechanism of myocyte turnover. This review will highlight the advances and landmark studies that opened new frontiers in cardiac regeneration

Redox Regulation of Heart Regeneration: An Evolutionary Tradeoff

Heart failure is a costly and deadly disease, affecting over 23 million patients worldwide, half of which die within 5 years of diagnosis. The pathophysiological basis of heart failure is the inability of the adult heart to regenerate lost or damaged myocardium. Although limited myocyte turnover does occur in the adult heart, it is insufficient for restoration of contractile function1-6. In contrast to lower vertebrates which can regenerate their myocardium through cardiomyocyte proliferation,7-13, adult mammalian heart cardiomyogenesis very limited1-5. Studies in the late 90s elegantly demonstrated that mammalian cardiomyocytes continue to divide for a few days after birth 14-16, only to undergo permanent cell cycle arrest shortly thereafter. Recently, we demonstrated that resection of up to 15% of the apex of the left ventricle of postnatal day 1 (P1) mice results in complete regeneration within 21 days following injury, without significant fibrosis and cardiac dysfunction17. Moreover, we described a similar regenerative response following ischemic myocardial infarction 18. This response was well characterized by robust cardiomyocyte proliferation, with gradual restoration of normal cardiac morphology and function. In addition to the histological evidence of proliferating myocytes, genetic fate-mapping studies confirmed that the majority of newly formed cardiomyocytes are derived from proliferation of preexisting cardiomyocytes17. Intriguingly, this regenerative capacity is lost by P7, after which injury results in the cardiomyocyte hypertrophy and scar-formation, which coincides with binucleation and cell cycle exit of cardiomyocytes 14, 19. An important approach to understanding the loss of regenerative ability of the mammalian heart is to first consider why, and not only how, this happens. The regenerative ability of the early postnatal heart following resection or ischemic infarction involves regeneration of the lost myocardium and vasculature with restoration of normal myocardial thickness and architecture, and long-term functional recovery. Why would the heart permanently forego such a remarkable regenerative program shortly after birth? The answer may lie in within the fundamental principal of evolutionary tradeoff

Multi-Investigator Letter on Reproducibility of Neonatal Heart Regeneration following Apical Resection

We appreciate the interest that Andersen et al. (2014) have shown in our work on neonatal cardiac regeneration. Their recent paper relates directly to resection methodology first presented by Porrello et al. (2011) and describes a failure to reproduce the observations made in that study regarding regeneration after resection. We are puzzled by the results and conclusion because in the hands of the seven different groups who authored this letter, this methodology has proved robust and reproducible and has been used in several ongoing studies across our different laboratories that are in various stages of completion (Heallen et al., [2013], as well as studies by the Lee, Takeuchi, and Nei groups that are currently under review). Importantly, several independent groups had similar observations using various types of neonatal injury (Strungs et al., 2013; Haubner et al., 2012; Naqvi et al., 2014; Jesty et al., 2012), where an increase in cardiomyocytes was also observed. Having carefully examined the study published by Andersen et al. (2014), it is our overall impression that methodological differences are likely to account for the difference in published results. Although it is difficult to draw clear conclusions about such differences without a detailed analysis of primary data, our impression is that variations in surgical technique, amount of resected myocardium, methods of quantification of resected and regenerated myocardium, and methods of assessment of myocyte proliferation form the basis of the differences seen. In particular, we used ventricular weight and surface area immediately after resection and 21 days later to assess the degree of injury and regeneration, while the Andersen group used HW/BW immediately after resection and ventricular weight 21 days later. Notably, in Figure 1E of the Andersen et al., 2014, paper, the amount of resected myocardium by ventricular weight 2 days after resection was in excess of 40%. We have not examined the effect of resection of such a large segment of the myocardium, but it is plausible that it not compatible with regeneration. We stand by the reproducibility of the initial report and we would be happy to assist Andersen et al. (2014) with various technical aspects of the neonatal apical resection method

Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer

Fibroblast Primary Cilia are Required for Cardiac Fibrosis

Background: The primary cilium is a singular cellular structure that extends from the surface of many cell types and plays crucial roles in vertebrate development, including that of the heart. Whereas ciliated cells have been described in developing heart, a role for primary cilia in adult heart has not been reported. This, coupled with the fact that mutations in genes coding for multiple ciliary proteins underlie polycystic kidney disease, a disorder with numerous cardiovascular manifestations, prompted us to identify cells in adult heart harboring a primary cilium and to determine whether primary cilia play a role in disease-related remodeling. Methods: Histological analysis of cardiac tissues from C57BL/6 mouse embryos, neonatal mice, and adult mice was performed to evaluate for primary cilia. Three injury models (apical resection, ischemia/reperfusion, and myocardial infarction) were used to identify the location and cell type of ciliated cells with the use of antibodies specific for cilia (acetylated tubulin, γ-tubulin, polycystin [PC] 1, PC2, and KIF3A), fibroblasts (vimentin, α-smooth muscle actin, and fibroblast-specific protein-1), and cardiomyocytes (α-actinin and troponin I). A similar approach was used to assess for primary cilia in infarcted human myocardial tissue. We studied mice silenced exclusively in myofibroblasts for PC1 and evaluated the role of PC1 in fibrogenesis in adult rat fibroblasts and myofibroblasts. Results: We identified primary cilia in mouse, rat, and human heart, specifically and exclusively in cardiac fibroblasts. Ciliated fibroblasts are enriched in areas of myocardial injury. Transforming growth factor β-1 signaling and SMAD3 activation were impaired in fibroblasts depleted of the primary cilium. Extracellular matrix protein levels and contractile function were also impaired. In vivo, depletion of PC1 in activated fibroblasts after myocardial infarction impaired the remodeling response. Conclusions: Fibroblasts in the neonatal and adult heart harbor a primary cilium. This organelle and its requisite signaling protein, PC1, are required for critical elements of fibrogenesis, including transforming growth factor β-1-SMAD3 activation, production of extracellular matrix proteins, and cell contractility. Together, these findings point to a pivotal role of this organelle, and PC1, in disease-related pathological cardiac remodeling and suggest that some of the cardiovascular manifestations of autosomal dominant polycystic kidney disease derive directly from myocardium-autonomous abnormalities

A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

10.1038/s41586-020-2228-6Nature5827811271-27

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone