Macrophage-derived extracellular vesicles alter cardiac recovery and metabolism in a rat heart model of donation after circulatory death.

Conditions to which the cardiac graft is exposed during transplantation with donation after circulatory death (DCD) can trigger the recruitment of macrophages that are either unpolarized (M0) or pro-inflammatory (M1) as well as the release of extracellular vesicles (EV). We aimed to characterize the effects of M0 and M1 macrophage-derived EV administration on post-ischaemic functional recovery and glucose metabolism using an isolated rat heart model of DCD. Isolated rat hearts were subjected to 20 min aerobic perfusion, followed by 27 min global, warm ischaemia or continued aerobic perfusion and 60 min reperfusion with or without intravascular administration of EV. Four experimental groups were compared: (1) no ischaemia, no EV; (2) ischaemia, no EV; (3) ischaemia with M0-macrophage-dervied EV; (4) ischaemia with M1-macrophage-derived EV. Post-ischaemic ventricular and metabolic recovery were evaluated. During reperfusion, ventricular function was decreased in untreated ischaemic and M1-EV hearts, but not in M0-EV hearts, compared to non-ischaemic hearts (p < 0.05). In parallel with the reduced functional recovery in M1-EV versus M0-EV ischaemic hearts, rates of glycolysis from exogenous glucose and oxidative metabolism tended to be lower, while rates of glycogenolysis and lactate release tended to be higher. EV from M0- and M1-macrophages differentially affect post-ischaemic cardiac recovery, potentially by altering glucose metabolism in a rat model of DCD. Targeted EV therapy may be a useful approach for modulating cardiac energy metabolism and optimizing graft quality in the setting of DCD.

ptx3a+ fibroblast/epicardial cells provide a transient macrophage niche to promote heart regeneration.

Macrophages conduct critical roles in heart repair, but the niche required to nurture and anchor them is poorly studied. Here, we investigated the macrophage niche in the regenerating heart. We analyzed cell-cell interactions through published single-cell RNA sequencing datasets and identified a strong interaction between fibroblast/epicardial (Fb/Epi) cells and macrophages. We further visualized the association of macrophages with Fb/Epi cells and the blockage of macrophage response without Fb/Epi cells in the regenerating zebrafish heart. Moreover, we found that ptx3a+ epicardial cells associate with reparative macrophages, and their depletion resulted in fewer reparative macrophages. Further, we identified csf1a expression in ptx3a+ cells and determined that pharmacological inhibition of the csf1a pathway or csf1a knockout blocked the reparative macrophage response. Moreover, we found that genetic overexpression of csf1a enhanced the reparative macrophage response with or without heart injury. Altogether, our studies illuminate a cardiac Fb/Epi niche, which mediates a beneficial macrophage response after heart injury.

Influence of a 7-day Transalpine Trail Run on cardiac biomarkers and myocardial function.

Intense physical exercise is known to increase cardiac biomarkers; however, it is unclear, whether this phenomenon is physiological, or if it indicates myocardial tissue injury. The aim of our study was to investigate the effects of seven consecutive days of excessive endurance exercise on continuous assessment of cardiac biomarkers, function, and tissue injury. During a 7-day trail-running competition (Transalpine Run, distance 267.4 km, altitude ascent/descent 15556/14450 m), daily blood samples were obtained for cardiac biomarkers (hs-TnT, NT-proBNP, and suppression of tumorigenicity-2 protein (ST2)) at baseline, after each stage and 24-48 h post-race. In addition, echocardiography was performed every second day, cardiac magnetic resonance imaging (CMR) before (n = 7) and after (n = 16) the race. Twelve (eight males) out of 17 healthy athletes finished all seven stages (average total finish time: 43 ± 8 h). Only NT-proBNP increased significantly (3.6-fold, p = 0.009) during the first stage and continued to increase during the race. Hs-TnT revealed an incremental trend during the first day (2.7-fold increase, p = 0.098) and remained within the pathological range throughout the race. ST2 levels did not change during the race. All cardiac biomarkers completely returned to physiological levels post-race. NT-proBNP kinetics correlated significantly with mild transient reductions in right ventricular function (assessed by TAPSE, tricuspid annular plane systolic function; r = -0.716; p = 0.014). No significant echocardiographic changes in LV dimensions, LV function, or relevant alterations in CMR were observed post-race. In summary, this study shows that prolonged, repetitive, high-volume exercise induced a transient, significant increase in NT-proBNP associated with right ventricular dysfunction without corresponding left ventricular functional or structural impairment.

Single-cell chromatin profiling reveals genetic programs activating proregenerative states in nonmyocyte cells.

Cardiac regeneration requires coordinated participation of multiple cell types whereby their communications result in transient activation of proregenerative cell states. Although the molecular characteristics and lineage origins of these activated cell states and their contribution to cardiac regeneration have been studied, the extracellular signaling and the intrinsic genetic program underlying the activation of the transient functional cell states remain largely unexplored. In this study, we delineated the chromatin landscapes of the noncardiomyocytes (nonCMs) of the regenerating heart at the single-cell level and inferred the cis-regulatory architectures and trans-acting factors that control cell type-specific gene expression programs. Moreover, further motif analysis and cell-specific genetic manipulations suggest that the macrophage-derived inflammatory signal tumor necrosis factor-α, acting via its downstream transcription factor complex activator protein-1, functions cooperatively with discrete transcription regulators to activate respective nonCM cell types critical for cardiac regeneration. Thus, our study defines the regulatory architectures and intercellular communication principles in zebrafish heart regeneration.

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery.

The human heart lacks significant regenerative capacity; thus, the solution to heart failure (HF) remains organ donation, requiring surgery and immunosuppression. The demand for constructed cardiac tissues (CCTs) to model and treat disease continues to grow. Recent advances in induced pluripotent stem cell (iPSC) manipulation, CRISPR gene editing, and 3D tissue culture have enabled a boom in iPSC-derived CCTs (iPSC-CCTs) with diverse cell types and architecture. Compared with 2D-cultured cells, iPSC-CCTs better recapitulate heart biology, demonstrating the potential to advance organ modeling, drug discovery, and regenerative medicine, though iPSC-CCTs could benefit from better methods to faithfully mimic heart physiology and electrophysiology. Here, we summarize advances in iPSC-CCTs and future developments in the vascularization, immunization, and maturation of iPSC-CCTs for study and therapy.

Distinct epicardial gene regulatory programs drive development and regeneration of the zebrafish heart.

Unlike the adult mammalian heart, which has limited regenerative capacity, the zebrafish heart fully regenerates following injury. Reactivation of cardiac developmental programs is considered key to successfully regenerating the heart, yet the regulation underlying the response to injury remains elusive. Here, we compared the transcriptome and epigenome of the developing and regenerating zebrafish epicardia. We identified epicardial enhancer elements with specific activity during development or during adult heart regeneration. By generating gene regulatory networks associated with epicardial development and regeneration, we inferred genetic programs driving each of these processes, which were largely distinct. Loss of Hif1ab, Nrf1, Tbx2b, and Zbtb7a, central regulators of the regenerating epicardial network, in injured hearts resulted in elevated epicardial cell numbers infiltrating the wound and excess fibrosis after cryoinjury. Our work identifies differences between the regulatory blueprint deployed during epicardial development and regeneration, underlining that heart regeneration goes beyond the reactivation of developmental programs.

Spatiotemporal development and the regulatory mechanisms of cardiac resident macrophages: Contribution in cardiac development and steady state.

Cardiac resident macrophages (CRMs) are integral components of the heart and play significant roles in cardiac development, steady-state, and injury. Advances in sequencing technology have revealed that CRMs are a highly heterogeneous population, with significant differences in phenotype and function at different developmental stages and locations within the heart. In addition to research focused on diseases, recent years have witnessed a heightened interest in elucidating the involvement of CRMs in heart development and the maintenance of cardiac function. In this review, we primarily concentrated on summarizing the developmental trajectories, both spatial and temporal, of CRMs and their impact on cardiac development and steady-state. Moreover, we discuss the possible factors by which the cardiac microenvironment regulates macrophages from the perspectives of migration, proliferation, and differentiation under physiological conditions. Gaining insight into the spatiotemporal heterogeneity and regulatory mechanisms of CRMs is of paramount importance in comprehending the involvement of macrophages in cardiac development, injury, and repair, and also provides new ideas and therapeutic methods for treating heart diseases.

Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript.

Zebrafish provide a translational model of human cardiac function. Their similar cardiac electrophysiology enables screening of human cardiac repolarization disorders, drug arrhythmogenicity, and novel antiarrhythmic therapeutics. However, while zebrafish cardiac repolarization is driven by delayed rectifier potassium channel current (IKr), the relative role of alternate channel transcripts is uncertain. While human ether-a-go-go-related-gene-1a (hERG1a) is the dominant transcript in humans, expression of the functionally distinct alternate transcript, hERG1b, modifies the electrophysiological and pharmacologic IKr phenotype. Studies of zebrafish IKr are frequently translated without consideration for the presence and impact of hERG1b in humans. Here, we performed phylogenetic analyses of all available KCNH genes from Actinopterygii (ray-finned fishes). Our findings confirmed zebrafish cardiac zkcnh6a as the paralog of human hERG1a (hKCNH2a), but also revealed evidence of a hERG1b (hKCNH2b)-like N-terminally truncated gene, zkcnh6b, in zebrafish. zkcnh6b is a teleost-specific variant that resulted from the 3R genome duplication. qRT-PCR showed dominant expression of zkcnh6a in zebrafish atrial and ventricular tissue, with low levels of zkcnh6b. Functional evaluation of zkcnh6b in a heterologous system showed no discernable function under the conditions tested, and no influence on zkcnh6a function during the zebrafish ventricular action potential. Our findings provide the first descriptions of the zkcnh6b gene, and show that, unlike in humans, zebrafish cardiac repolarization does not rely upon co-assembly of zERG1a/zERG1b. Given that hERG1b modifies IKr function and drug binding in humans, our findings highlight the need for consideration when translating hERG variant effects and toxicological screens in zebrafish, which lack a functional hERG1b-equivalent gene.

Myocardial edema, inflammation, and injury in human heart donated after circulatory death are sensitive to warm ischemia and subsequent cold storage.

BACKGROUND: Single-dose del Nido solution was recently used in human donation after circulatory death (DCD) heart procurement. We compared the effect of del Nido cardioplegia on myocardial edema, inflammatory response, and injury in human DCD hearts and human donation after brain death (DBD) hearts with different warm ischemic times (WIT) and subsequent cold saline storage times (CST). METHODS: A total of 24 human hearts, including 6 in the DBD group and 18 in the DCD group-were procured for the research study. The DCD group was divided into 3 subgroups based on WIT: 20, 40, and ≥60 minutes. All hearts received 1 L of del Nido cardioplegia before being placed in cold saline for 6 hours. Left ventricular biopsies were performed at 0, 2, 4, and 6 hours. Temporal changes in myocardial edema, inflammatory cytokines (TNF-α, IL-6, and IL-1ß), and histopathology injury scores were compared between the DBD and DCD groups. RESULTS: DCD hearts showed more profound changes in myocardial edema, inflammation, and injury than DBD hearts at baseline and subsequent CST. The DCD heart with WIT of 20 and 40 minutes with CST of 4 and 2 hours, respectively, appeared to have limited myocardial edema, inflammation, and injury. DCD hearts with WIT ≥60 minutes showed severe myocardial edema, inflammation, and injury at baseline and subsequent CST. CONCLUSIONS: Single-dose cold del Nido cardioplegia and subsequent cold normal saline storage can preserve both DCD and DBD hearts. DCD hearts have been shown to be able to tolerate a WIT of 20 minutes and subsequent CST of 4 hours without experiencing significant myocardial edema, inflammation, and injury.

Pathways and morphologic pattern of blood supply of epicardial ganglionated nerve plexus.

Detailed cardiac neuroanatomy is critical for understanding cardiac function and its pathology. However, there remains a significant gap in knowledge regarding the blood supply to the intrinsic cardiac ganglionated plexus (GP). This study addresses this by mapping the routes and morphological pattern of blood supply to the epicardial GP in a large-animal pig model (Sus scrofa domesticus). Twenty-five domestic pigs were used in the study. We demonstrate that the epicardial ganglionated nerves receive blood from both coronary and extra-cardiac arteries. The coronary arterial branches supply blood to all five subplexuses constituting the epicardial GP. In contrast, the branches of extra-cardiac arteries supply blood to target heart areas: 1) the venous part of the heart hilum on the left atrium, 2) the walls of the sinuses of the right cranial (superior cava) and 3) pulmonary veins. Uniformly, epicardial nerves and ganglia are supplied with blood via a sole epineurial arteriole which, in most cases, is the fifth/sixth-order branch of the coronary arteries. The extra-cardiac arteries supplying blood to the epicardial GP accompanied the mediastinal nerves entering the epicardium within the limits of the heart hilum. Together, the dual and triple blood supply of the epicardial nerves and ganglia suggests a protective role from an ischemic event and/or ischemic heart disease. STUCTURED ABSTRACT: This study details the anatomy of the blood supply of epicardial ganglionated nerve plexus, from which nerve fibres extend to the myocardium, heart conduction system, coronary vessels, and endocardium, in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our observations demonstrate that the epicardial nerves and ganglia receive blood from both coronary and extra-cardiac arteries. The multi-source blood supply to the cardiac nerves and ganglia may offer protection against myocardial infarction ant other ischemic heart disorders.

Fulfilling the Promise of RNA Therapies for Cardiac Repair and Regeneration.

The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in vivo now offers unprecedented possibilities for obtaining RNA-based therapeutics. For the heart, RNA therapies can be developed that stimulate endogenous repair after cardiac damage. Applications in this area include acute cardioprotection after ischemia or cancer chemotherapy, therapeutic angiogenesis to promote new blood vessel formation, regeneration to form new cardiac mass, and editing of mutations to cure inherited cardiac disease. While the potential of RNA therapeutics for all these conditions is exciting, the field is still in its infancy. A number of roadblocks need to be overcome for RNA therapies to become effective, in particular, related to the problem of delivering RNA medicines into the cells and targeting them specifically to the heart.

Polarizing Macrophage Functional Phenotype to Foster Cardiac Regeneration.

There is an increasing interest in understanding the connection between the immune and cardiovascular systems, which are highly integrated and communicate through finely regulated cross-talking mechanisms. Recent evidence has demonstrated that the immune system does indeed have a key role in the response to cardiac injury and in cardiac regeneration. Among the immune cells, macrophages appear to have a prominent role in this context, with different subtypes described so far that each have a specific influence on cardiac remodeling and repair. Similarly, there are significant differences in how the innate and adaptive immune systems affect the response to cardiac damage. Understanding all these mechanisms may have relevant clinical implications. Several studies have already demonstrated that stem cell-based therapies support myocardial repair. However, the exact role that cardiac macrophages and their modulation may have in this setting is still unclear. The current need to decipher the dual role of immunity in boosting both heart injury and repair is due, at least for a significant part, to unresolved questions related to the complexity of cardiac macrophage phenotypes. The aim of this review is to provide an overview on the role of the immune system, and of macrophages in particular, in the response to cardiac injury and to outline, through the modulation of the immune response, potential novel therapeutic strategies for cardiac regeneration.

Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration.

Zebrafish exhibit a robust ability to regenerate their hearts following injury, and the immune system plays a key role in this process. We previously showed that delaying macrophage recruitment by clodronate liposome (-1d_CL, macrophage-delayed model) impairs neutrophil resolution and heart regeneration, even when the infiltrating macrophage number was restored within the first week post injury (Lai et al., 2017). It is thus intriguing to learn the regenerative macrophage property by comparing these late macrophages vs. control macrophages during cardiac repair. Here, we further investigate the mechanistic insights of heart regeneration by comparing the non-regenerative macrophage-delayed model with regenerative controls. Temporal RNAseq analyses revealed that -1d_CL treatment led to disrupted inflammatory resolution, reactive oxygen species homeostasis, and energy metabolism during cardiac repair. Comparative single-cell RNAseq profiling of inflammatory cells from regenerative vs. non-regenerative hearts further identified heterogeneous macrophages and neutrophils, showing alternative activation and cellular crosstalk leading to neutrophil retention and chronic inflammation. Among macrophages, two residential subpopulations (hbaa+ Mac and timp4.3+ Mac 3) were enriched only in regenerative hearts and barely recovered after +1d_CL treatment. To deplete the resident macrophage without delaying the circulating macrophage recruitment, we established the resident macrophage-deficient model by administrating CL earlier at 8 d (-8d_CL) before cryoinjury. Strikingly, resident macrophage-deficient zebrafish still exhibited defects in revascularization, cardiomyocyte survival, debris clearance, and extracellular matrix remodeling/scar resolution without functional compensation from the circulating/monocyte-derived macrophages. Our results characterized the diverse function and interaction between inflammatory cells and identified unique resident macrophages prerequisite for zebrafish heart regeneration.

Cardiac Transplantation: Physiology and Natural History of the Transplanted Heart.

Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short- and long-term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long-term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health-related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age-matched healthy subjects. Several factors, including alterations in central hemodynamics, HT-related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high-intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719-4765, 2023.

Morphological and Functional Analysis of Cardiac Ameliorations in Elderly Rats Supplemented with a Magnolol Extract Complex / Análisis Morfológico y Funcional de las Mejoras Cardíacas en Ratas Ancianas Suplementadas con un Complejo de Extracto de Magnolol

SUMMARY: Magnolia bark extract supplementation has an anti-oxidative role in mammalians. However, its role in physiological aged-associated heart insufficiency is not known yet. Therefore, we investigated the effects of a magnolia bark complex, including magnolol and honokiol components (MAHOC), in elderly rat hearts (24-month-old aged group). One group of aged rats was supplemented with MAHOC (400 mg/kg/d, for 12 weeks) besides the standard rat diet while the second group of elderly rats and adult rats (to 6-month- old adult-group) were only fed with the standard rat diet. The morphological analysis using light microscopy has shown marked myofibrillar losses, densely localized fibroblasts, vacuolizations, infiltrated cell accumulations, and collagen fibers in the myocardium of the elderly rats compared to the adults. We also detected a markedly increased amount of degenerated cardiomyocytes including the euchromatic nucleus. The MAHOC supplementation of the elderly rats provided marked ameliorations in these abnormal morphological changes in the heart tissue. Furthermore, electrophysiological analysis of electrocardiograms (ECGs) in the supplemented group showed significant attenuations in the prolonged durations of P-waves, QRS-complexes, QT-intervals, and low heart rates compared to the unsupplemented elderly group. The biochemical analysis also showed significant attenuations in the activity of arylesterase and total antioxidant status in the myocardium of the supplemented group. We further determined significant attenuations in the activity of a mitochondrial enzyme succinate dehydrogenase, known as a source of reactive oxygen species (ROS), and the decreased level of ATP/ADP in the heart homogenates of the supplemented group. Moreover, under in vitro conditions by using an aging-mimicked cardiac cell line induced by D-galactose, we demonstrated that MAHOC treatment could provide prevention of depolarization in mitochondria membrane potential and high-level ROS production. Overall, our data presented significant myocardial ameliorations in physiological aging-associated morphological alterations parallel to the function and biochemical attenuations with MAHOC supplementation, at most, through recoveries in mitochondria.

La suplementación con extracto de corteza de magnolia tiene un papel antioxidante en los mamíferos, sin embargo, su rol en la insuficiencia cardíaca asociada al envejecimiento fisiológico aún no se conoce. Por lo anterior, investigamos los efectos de un complejo de corteza de magnolia, incluidos los componentes magnolol y honokiol (MAHOC), en corazones de ratas seniles (grupo de edad de 24 meses). La alimentación de grupo de ratas seniles se complementó con MAHOC (400 mg/kg/d, durante 12 semanas) además de la dieta estándar, mientras que el segundo grupo de ratas seniles y ratas adultas (hasta el grupo de adultos de 6 meses) solo recibió la dieta estándar para ratas. El análisis morfológico mediante microscopía óptica ha mostrado marcadas pérdidas miofibrilares, fibroblastos densamente localizados, vacuolizaciones, acumulaciones de células infiltradas y fibras de colágeno en el miocardio de las ratas seniles en comparación con las adultas. También detectamos una cantidad notablemente mayor de cardiomiocitos degradados, incluido el núcleo eucromático. La suplementación con MAHOC de las ratas seniles proporcionó mejoras marcadas en estos cambios morfológicos anormales en el tejido cardiaco. Por otra parte, el análisis de los electrocardiogramas (ECG) en el grupo suplementado mostró atenuaciones significativas en las duraciones prolongadas de las ondas P, los complejos QRS, los intervalos QT y las frecuencias cardíacas bajas, en comparación con el grupo de ratas seniles sin suplementación alimenticia. El análisis bioquímico también mostró atenuaciones significativas en la actividad de la arilesterasa y el estado antioxidante total en el miocardio del grupo suplementado. Determinamos además atenuaciones significativas en la actividad de la enzima mitocondrial succinato deshidrogenasa, conocida como fuente de especies reactivas de oxígeno (ROS), y la disminución del nivel de ATP/ADP en los homogeneizados de corazón del grupo suplementado. Además, en condiciones in vitro mediante el uso de una línea de células cardíacas, imitando el envejecimiento inducido por D- galactosa, demostramos que el tratamiento con MAHOC podría prevenir la despolarización en el potencial de membrana de las mitocondrias y la producción de ROS de alto nivel. En general, nuestros datos presentaron mejoras miocárdicas significativas en alteraciones morfológicas asociadas con el envejecimiento fisiológico paralelas a la función y atenuaciones bioquímicas con la suplementación con MAHOC, como máximo, a través de recuperaciones en las mitocondrias.

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis.

BACKGROUND: Structural changes caused by spinal curvature may impact the organs within the thoracic cage, including the heart. Cardiac abnormalities in patients with idiopathic scoliosis are often studied post-corrective surgery or secondary to diseases. To investigate cardiac structure, function and outcomes in participants with scoliosis, phenotype and imaging data of the UK Biobank (UKB) adult population cohort were analysed. METHODS: Hospital episode statistics of 502 324 adults were analysed to identify participants with scoliosis. Summary 2D cardiac phenotypes from 39 559 cardiac MRI (CMR) scans were analysed alongside a 3D surface-to-surface (S2S) analysis. RESULTS: A total of 4095 (0.8%, 1 in 120) UKB participants were identified to have all-cause scoliosis. These participants had an increased lifetime risk of major adverse cardiovascular events (MACEs) (HR=1.45, p<0.001), driven by heart failure (HR=1.58, p<0.001) and atrial fibrillation (HR=1.54, p<0.001). Increased radial and decreased longitudinal peak diastolic strain rates were identified in participants with scoliosis (+0.29, Padj <0.05; -0.25, Padj <0.05; respectively). Cardiac compression of the top and bottom of the heart and decompression of the sides was observed through S2S analysis. Additionally, associations between scoliosis and older age, female sex, heart failure, valve disease, hypercholesterolemia, hypertension and decreased enrolment for CMR were identified. CONCLUSION: The spinal curvature observed in participants with scoliosis alters the movement of the heart. The association with increased MACE may have clinical implications for whether to undertake surgical correction. This work identifies, in an adult population, evidence for altered cardiac function and an increased lifetime risk of MACE in participants with scoliosis.

Microcirculatory changes as a hallmark of aging in the heart and kidney / Cambios microcirculatorios como sello distintivo del envejecimiento en el corazón y riñón

SUMMARY: Changes in the microcirculation of multiple tissues and organs have been implicated as a possible mechanism in physiological aging. In particular, vascular endothelial growth factor is a secretory protein responsible for regulating angiogenesis via altering endothelial proliferation, survival, migration, extracellular matrix degradation and cell permeability. The aim of the present study was to evaluate the role of vascular endothelial growth factor in the progression of morphological alterations caused by physiological aging in the heart and kidney and to examine its relation to changes in capillary density. We used two age groups of healthy Wistar rats - 6- and 12-month- old. The expression of vascular endothelial growth factor was examined through immunohistochemistry and immunofluorescence and assessed semi-quantitatively. Changes in capillary density were evaluated statistically and correlated with the expression of vascular endothelial growth factor. We reported stronger immunoreactivity for vascular endothelial growth factor in the left compared to the right ventricle and also observed an increase in its expression in both ventricles in older animals. Contrasting results were reported for the renal cortex and medulla. Capillary density decreased statistically in all examined structures as aging progressed. The studied correlations were statistically significant in the two ventricles in 12-month-old animals and in the renal cortex of both age groups. Our results shed light on some changes in the microcirculation that take place as aging advances and likely contribute to impairment in the function of the examined organs.

Los cambios en la microcirculación de múltiples tejidos y órganos se han implicado como un posible mecanismo en el envejecimiento fisiológico. En particular, el factor de crecimiento endotelial vascular es una proteína secretora responsable de regular la angiogénesis mediante la alteración de la proliferación endotelial, la supervivencia, la migración, la degradación de la matriz extracelular y la permeabilidad celular. El objetivo del presente estudio fue evaluar el papel del factor de crecimiento del endotelio vascular en la progresión de las alteraciones morfológicas causadas por el envejecimiento fisiológico en el corazón y riñón y examinar su relación con los cambios en la densidad capilar. Utilizamos dos grupos de ratas Wistar sanas: 6 y 12 meses de edad. La expresión del factor de crecimiento del endotelio vascular se examinó mediante inmunohistoquímica e inmunofluorescencia y se evaluó semicuantitativamente. Los cambios en la densidad capilar se evaluaron estadísticamente y se correlacionaron con la expresión del factor de crecimiento del endotelio vascular. Informamos una inmunorreactividad más fuerte para el factor de crecimiento endotelial vascular en el ventrículo izquierdo en comparación con el derecho y también observamos un aumento en su expresión en ambos ventrículos en animales mayores. Se informaron resultados contrastantes para la corteza renal y la médula. La densidad capilar disminuyó estadísticamente en todas las estructuras examinadas a medida que avanzaba el envejecimiento. Las correlaciones estudiadas fueron estadísticamente significativas en los dos ventrículos en animales de 12 meses y en la corteza renal de ambos grupos de edad. Nuestros resultados arrojan luz sobre algunos cambios en la microcirculación que tienen lugar a medida que avanza el envejecimiento y probablemente contribuyan a un deterioro en la función de los órganos examinados.

The role of macrophage subsets in and around the heart in modulating cardiac homeostasis and pathophysiology.

Cardiac and pericardial macrophages contribute to both homeostatic and pathophysiological processes. Recent advances have identified a vast repertoire of these macrophage populations in and around the heart - broadly categorized into a CCR2+/CCR2- dichotomy. While these unique populations can be further distinguished by origin, localization, and other cell surface markers, further exploration into the role of cardiac and pericardial macrophage subpopulations in disease contributes an additional layer of complexity. As such, novel transgenic models and exogenous targeting techniques have been employed to evaluate these macrophages. In this review, we highlight known cardiac and pericardial macrophage populations, their functions, and the experimental tools used to bolster our knowledge of these cells in the cardiac context.

Malat1 deficiency prevents neonatal heart regeneration by inducing cardiomyocyte binucleation.

The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative macrophages and angiogenesis. Although the process of regeneration has been well studied in the neonatal mouse, the molecular mechanisms that define the switch between regenerative and nonregenerative cardiomyocytes are not well understood. Here, using in vivo and in vitro approaches, we identified the lncRNA Malat1 as a key player in postnatal cardiac regeneration. Malat1 deletion prevented heart regeneration in mice after myocardial infarction on postnatal day 3 associated with a decline in cardiomyocyte proliferation and reparative angiogenesis. Interestingly, Malat1 deficiency increased cardiomyocyte binucleation even in the absence of cardiac injury. Cardiomyocyte-specific deletion of Malat1 was sufficient to block regeneration, supporting a critical role of Malat1 in regulating cardiomyocyte proliferation and binucleation, a landmark of mature nonregenerative cardiomyocytes. In vitro, Malat1 deficiency induced binucleation and the expression of a maturation gene program. Finally, the loss of hnRNP U, an interaction partner of Malat1, induced similar features in vitro, suggesting that Malat1 regulates cardiomyocyte proliferation and binucleation by hnRNP U to control the regenerative window in the heart.

Unlocking cardiomyocyte renewal potential for myocardial regeneration therapy.

Cardiovascular disease remains the leading cause of mortality worldwide. Cardiomyocytes are irreversibly lost due to cardiac ischemia secondary to disease. This leads to increased cardiac fibrosis, poor contractility, cardiac hypertrophy, and subsequent life-threatening heart failure. Adult mammalian hearts exhibit notoriously low regenerative potential, further compounding the calamities described above. Neonatal mammalian hearts, on the other hand, display robust regenerative capacities. Lower vertebrates such as zebrafish and salamanders retain the ability to replenish lost cardiomyocytes throughout life. It is critical to understand the varying mechanisms that are responsible for these differences in cardiac regeneration across phylogeny and ontogeny. Adult mammalian cardiomyocyte cell cycle arrest and polyploidization have been proposed as major barriers to heart regeneration. Here we review current models about why adult mammalian cardiac regenerative potential is lost including changes in environmental oxygen levels, acquisition of endothermy, complex immune system development, and possible cancer risk tradeoffs. We also discuss recent progress and highlight conflicting reports pertaining to extrinsic and intrinsic signaling pathways that control cardiomyocyte proliferation and polyploidization in growth and regeneration. Uncovering the physiological brakes of cardiac regeneration could illuminate novel molecular targets and offer promising therapeutic strategies to treat heart failure.