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Heme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword because they can damage the kidney in certain settings. Although such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analog, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury after the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; auto-oxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury after myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.

Preeclampsia (PE), new-onset hypertension during pregnancy, affects up to 10% of pregnancies worldwide. Despite being the leading cause of maternal and fetal morbidity and mortality, PE has no cure beyond the delivery of the fetal-placental unit. Although the exact pathogenesis of PE is unclear, there is a strong correlation between chronic immune activation; intrauterine growth restriction; uterine artery resistance; dysregulation of the renin-angiotensin system. Which contributes to renal dysfunction; and the resulting hypertension during pregnancy. The genesis of PE is thought to begin with insufficient trophoblast invasion leading to reduced spiral artery remodeling, resulting in decreased placental perfusion and thereby causing placental ischemia. The ischemic placenta releases factors that shower the endothelium and contribute to peripheral vasoconstriction and chronic immune activation and oxidative stress. Studies have shown imbalances in proinflammatory and anti-inflammatory cell types in women with PE and in animal models used to examine mediators of a PE phenotype during pregnancy. T cells, B cells, and natural killer cells have all emerged as potential mediators contributing to the production of vasoactive factors, renal and endothelial dysfunction, mitochondrial dysfunction, and hypertension during pregnancy. The chronic immune activation seen in PE leads to a higher risk for other diseases, such as cardiovascular disease, CKD, dementia during the postpartum period, and PE during a subsequent pregnancy. The purpose of this review is to highlight studies demonstrating the role that different lymphoid cell populations play in the pathophysiology of PE. Moreover, we will discuss treatments focused on restoring immune balance or targeting specific immune mediators that may be potential strategies to improve maternal and fetal outcomes associated with PE.

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

Kidney disease represents a global health burden of increasing prevalence and is an independent risk factor for cardiovascular disease. Myeloid cells are a major cellular compartment of the immune system; they are found in the healthy kidney and in increased numbers in the damaged and/or diseased kidney, where they act as key players in the progression of injury, inflammation and fibrosis. They possess enormous plasticity and heterogeneity, adopting different phenotypic and functional characteristics in response to stimuli in the local milieu. Though this inherent complexity remains to be fully understood in the kidney, advances in single-cell genomics promises to change this. Specifically, single-cell RNA sequencing (scRNA-seq) has had a transformative effect on kidney research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput, and subsequent generation of cell atlases. Moving forward, combining scRNA- and single-nuclear RNA-seq with greater resolution spatial transcriptomics will allow spatial mapping of kidney disease of varying aetiology to further reveal the patterning of immune cells and non-immune renal cells.This review summarises the roles of myeloid cells in kidney health and disease, the experimental workflow in currently available scRNA-seq technologies and published findings using scRNA-seq in the context of myeloid cells and the kidney.

Seminal works have now revealed the gut microbiota is connected with several diseases, including renal disorders. The balance between optimal and dysregulated host-microbiota interactions has completely changed our understanding of immunity and inflammation. Kidney injury is associated with accumulation of uremic toxins in the intestine, augmented intestinal permeability, and systemic inflammation. Intestinal bacteria can signal through innate receptors and induce immune cell activation in the lamina propria and release of inflammatory mediators into the bloodstream . But the gut microbiota can also modulate immune functions through soluble products as short-chain fatty acids (SCFAs). The three most common SCFAs are propionate, butyrate, and acetate, which can signal through specific G-protein coupled receptors (GPCRs), such as GPR43, GPR41, and GPR109a, expressed on the surface of epithelial, myeloid, endothelial, and immune cells, among others. The triggered signaling can change cell metabolism, immune cell activation, and cell death. In this study, we reviewed the gut-kidney axis, how kidney cells can sense SCFAs, and its implication in kidney diseases.

Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For more than half a century, researchers have demonstrated that immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that proinflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFN-γ), in particular, as an important cytokine that modulates immune responses, has been recently identified as a critical regulator of blood pressure by several groups, including us. In this review, we focus on exploring the role of IFN-γ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFN-γ in hypertension through global knockout studies and related downstream signaling pathways that IFN-γ production from CD8(+) T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.

Over 20 years after the introduction of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, CKD remains a major public health burden with limited therapeutic options to halt or slow kidney disease progression at all ages. The consensus is that oxidative stress contributes to CKD development and progression. Yet, to date, there is no clear evidence that broad use of antioxidant therapy provides a beneficial effect in CKD. Understanding the specific pathophysiologic mechanisms in those who are genetically most susceptible to oxidative stress is a crucial step to inform therapy in an individualized medicine approach, considering differing exposures and risks across the life span. Glutathione-S-transferase μ 1 (GSTM1) is a phase 2 enzyme involved in inactivation of reactive oxygen species and metabolism of xenobiotics. In particular, those with the highly prevalent GSTM1 null genotype (GSTM1[0/0]) may be more susceptible to kidney disease progression, due to impaired capacity to handle the increased oxidative stress burden in disease states, and might specifically benefit from therapy that targets the redox imbalance mediated by loss of the GSTM1 enzyme. In this review, we will discuss the studies implicating the role of GSTM1 deficiency in kidney and related diseases from experimental rodent models to humans, from the prenatal period through senescence, and the potential underlying mechanism.

Chronic Kidney Disease (CKD) represents the 9th most common cause of death in the U.S(1), but despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and non-metabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of triglyceride and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.

Sphingolipids are now considered not only as constitutional components of the cellular membrane but also as essential bioactive factors regulating development and physiological functions. Ceramide is a vital intermediate of sphingolipid metabolism, synthesized by de novo and salvage pathways, producing multiple types of sphingolipids and their metabolites. Although mutations in gene encoding enzymes regulating sphingolipid synthesis and metabolism cause distinct diseases, an abnormal sphingolipid metabolism contributes to various pathological conditions, including kidney disease. Excessive accumulation of glycosphingolipids and promotion of the ceramide salvage and sphingosine-1-phosphate (S1P) pathways are found in the damaged kidney. Acceleration of the sphingosine kinase/S1P/S1P receptor (SphK/S1P/S1PR) axis plays a central role in deteriorating kidney functions. The SphK/S1P/S1PR signaling impairment is also found during pregnancy complications such as preeclampsia and intrauterine growth restriction (IUGR). This mini-review discusses the current state of knowledge regarding the role of sphingolipid metabolism on kidney diseases and the possible involvement of preeclampsia and IUGR conditions.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 10%. PCOS is diagnosed by the presence of at least two of these three criteria: hyperandrogenemia, oligo- or anovulation, and polycystic ovaries. The most common type (80%) of PCOS includes hyperandrogenemia. PCOS is also characterized by obesity or overweight (in 80% of US women with PCOS), insulin resistance with elevated plasma insulin but not necessarily hyperglycemia, dyslipidemia, proteinuria, and elevated BP. Although elevated compared with age-matched controls, BP may not reach levels considered treatable according to the current clinical hypertension guidelines. However, it is well known that elevated BP, even modestly so, increases the risk of cardiovascular disease. We have developed a model of hyperandrogenemia in rodents that mimics the characteristics of PCOS in women, with increases in body weight, insulin resistance, dyslipidemia, andproteinuria and elevated BP. This review discusses potential mechanisms responsible for the elevated BP in the adult and aging PCOS rat model that may be extrapolated to women with PCOS.

Salt-sensitive hypertension is a major risk factor for cardiovascular morbidity and mortality. The pathophysiologic mechanisms leading to different individual BP responses to changes in dietary salt remain elusive. Research in the last two decades revealed that the immune system plays a critical role in the development of hypertension and related end organ damage. Moreover, sodium accumulates nonosmotically in human tissue, including the skin and muscle, shifting the dogma on body sodium balance and its regulation. Emerging evidence suggests that high concentrations of extracellular sodium can directly trigger an inflammatory response in antigen-presenting cells (APCs), leading to hypertension and vascular and renal injury. Importantly, sodium entry into APCs is mediated by the epithelial sodium channel (ENaC). Although the role of the ENaC in renal regulation of sodium excretion and BP is well established, these new findings imply that the ENaC may also exert BP modulatory effects in extrarenal tissue through an immune-dependent pathway. In this review, we discuss the recent advances in our understanding of the pathophysiology of salt-sensitive hypertension with a particular focus on the roles of APCs and the extrarenal ENaC.

Bilirubin is the end product of the catabolism of heme via the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of heme, and biliverdin is rapidly reduced to bilirubin by the enzyme biliverdin reductase (BVR). Bilirubin has long been thought of as a toxic product that is only relevant to health when blood levels are severely elevated, such as in clinical jaundice. The physiologic functions of bilirubin correlate with the growing body of evidence demonstrating the protective effects of serum bilirubin against cardiovascular and metabolic diseases. Although the correlative evidence suggests a protective effect of serum bilirubin against many diseases, the mechanism by which bilirubin offers protection against cardiovascular and metabolic diseases remains unanswered. We recently discovered a novel function for bilirubin as a signaling molecule capable of activating the peroxisome proliferator-activated receptor α (PPARα) transcription factor. This review summarizes the new finding of bilirubin as a signaling molecule and proposes several mechanisms by which this novel action of bilirubin may protect against cardiovascular and kidney diseases.

Single-cell RNA sequencing (scRNA-seq) is a powerful technology that allows for the identification of minority cell types in complex tissues, such as immune cells in the kidney. Previously, gene expression from infrequent cell types was missed using bulk RNA-sequencing methods due to an averaging effect. Additionally, single-cell RNA sequencing facilitates assignment of cell origin in a sample, a shortcoming of previous bulk sequencing technologies. Thus, scRNA-seq is ideal to study the immune cell landscape and the alloimmune response in the human kidney transplant. However, there are few studies published to date. Macrophages are known to play an important role in health and disease in the kidney. Furthermore, it is known that macrophages play key roles in rejection of the kidney transplant. The definition, ontogeny, and function of these cells is complex and nomenclature has evolved as new technologies have become available. In this review, an overview of monocyte and macrophage nomenclature, ontogeny, and function with a specific focus on kidney transplantation is provided with novel scRNA-seq findings included. Single-cell RNA sequencing offers an unbiased transcriptional approach to defining macrophages and provides insights into macrophage ontogeny and function not possible with contemporary methods.

Olfactory receptors (ORs) represent the largest gene family in the human genome. Despite their name, functions exist for these receptors outside of the nose. Among the tissues known to take advantage of OR signaling is the kidney. From mouse to man, the list of renal ORs continues to expand, and they have now been linked to a variety of processes involved in the maintenance of renal homeostasis, including the modulation of blood pressure, response to acidemia, and the development of diabetes. In this review, we highlight the recent progress made on the growing appreciation for renal ORs in physiology and pathophysiology.

Congenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left‐sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic valve, coarctation of the aorta, and interrupted aortic arch. These defects can arise in isolation or as a component of a defined syndrome; however, nonsyndromic defects are often observed in multiple family members and associated with high sibling recurrence risk. This clear evidence for a heritable basis has driven a lengthy search for disease‐causing variants that has uncovered both rare and common variants in genes that, when perturbed in cardiac development, can result in LSOLs. Despite advancements in genetic sequencing platforms and broadening use of exome sequencing, the currently accepted LSOL‐associated genes explain only 10% to 20% of patients. Further, the combinatorial effects of common and rare variants as a cause of LSOLs are emerging. In this review, we highlight the genes and variants associated with the different LSOLs and discuss the strengths and weaknesses of the present genetic associations. Furthermore, we discuss the research avenues needed to bridge the gaps in our current understanding of the genetic basis of nonsyndromic congenital heart disease.

The myocardium consists of different cell types, of which endothelial cells, cardiomyocytes, and fibroblasts are the most abundant. Communication between these different cell types, also called paracrine signaling, is essential for normal cardiac function, but also important in cardiac remodeling and heart failure. Systematic studies on the expression of ligands and their corresponding receptors in different cell types showed that for 60% of the expressed ligands in a particular cell, the receptor is also expressed. The fact that many ligand‐receptor pairs are present in most cells, including the major cell types in the heart, indicates that autocrine signaling is a widespread phenomenon. Autocrine signaling in cardiac remodeling and heart failure is involved in all pathophysiological mechanisms generally observed: hypertrophy, fibrosis, angiogenesis, cell survival, and inflammation. Herein, we review ligand‐receptor pairs present in the major cardiac cell types based on RNA‐sequencing expression databases, and we review current literature on extracellular signaling proteins with an autocrine function in the heart; these include C‐type natriuretic peptide, fibroblast growth factors 2, F21, and 23, macrophage migration inhibitory factor, heparin binding–epidermal growth factor, angiopoietin‐like protein 2, leptin, adiponectin, follistatin‐like 1, apelin, neuregulin 1, vascular endothelial growth factor, transforming growth factor β, wingless‐type integration site family, member 1‐induced secreted protein‐1, interleukin 11, connective tissue growth factor/cellular communication network factor, and calcitonin gene‒related peptide. The large number of autocrine signaling factors that have been studied in the literature supports the concept that autocrine signaling is an essential part of myocardial biology and disease.

The proximal tubule relies on oxidative mitochondrial metabolism to meet its energy needs and has limited capacity for glycolysis, which makes it uniquely susceptible to damage during Acute Kidney Injury, especially after ischemia and anoxia. In that setting, mitochondrial ATP production is initially decreased by several mechanisms, including fatty acid-induced uncoupling and inhibition of respiration related to changes in the shape and volume of mitochondria. Glycolysis initially is insufficient as a source of ATP to protect the cells and mitochondrial function, but supplementation of tricarboxylic acid cycle intermediates, augments anaerobic ATP production and improves recovery of mitochondrial oxidative metabolism. Incomplete recovery is characterized by defects of respiratory enzymes and lipid metabolism. During the transition to Chronic Kidney Disease (CKD), tubular cells atrophy but maintain high expression of glycolytic enzymes and there is decreased fatty acid oxidation. These metabolic changes may be amenable to a number of therapeutic interventions.

Coronary artery disease remains the leading cause of death globally and is a major burden to every health system in the world. There have been significant improvements in risk modification, treatments, and mortality; however, our ability to detect asymptomatic disease for early intervention remains limited. Recent discoveries regarding the inflammatory nature of atherosclerosis have prompted investigation into new methods of diagnosis and treatment of coronary artery disease. This article reviews some of the highlights of the important developments in cardioimmunology and summarizes the clinical evidence linking the immune system and atherosclerosis. It provides an overview of the major serological biomarkers that have been associated with atherosclerosis, noting the limitations of these markers attributable to low specificity, and then contrasts these serological markers with the circulating immune cell subtypes that have been found to be altered in coronary artery disease. This review then outlines the technique of mass cytometry and its ability to provide high‐dimensional single‐cell data and explores how this high‐resolution quantification of specific immune cell subpopulations may assist in the diagnosis of early atherosclerosis in combination with other complimentary techniques such as single‐cell RNA sequencing. We propose that this improved specificity has the potential to transform the detection of coronary artery disease in its early phases, facilitating targeted preventative approaches in the precision medicine era.

Ischemia/reperfusion injury is a complex molecular cascade that causes deleterious cellular damage and organ dysfunction. Stroke, sudden cardiac arrest, and acute myocardial infarction are the most common causes of ischemia/reperfusion injury without effective pharmacologic therapies. Existing preclinical evidence suggests that histone deacetylase inhibitors may be an efficacious, affordable, and clinically feasible therapy that can improve neurologic and cardiac outcomes following ischemia/reperfusion injury. In this review, we discuss the pathophysiology and epigenetic modulations of ischemia/reperfusion injury and focus on the neuroprotective and cardioprotective effects of histone deacetylase inhibitors . We also summarize the protective effects of histone deacetylase inhibitors for other vital organs and highlight the key research priorities for their successful translation to the bedside.

Common variants in the APOL1 gene are associated with an increased risk of nondiabetic kidney disease in individuals of African ancestry. Mechanisms by which APOL1 variants mediate kidney disease pathogenesis are not well understood. Amino acid changes resulting from the kidney disease–associated APOL1 variants alter the three-dimensional structure and conformational dynamics of the C-terminal α-helical domain of the protein, which can rationalize the functional consequences. Understanding the three-dimensional structure of the protein, with and without the risk variants, can provide insights into the pathogenesis of kidney diseases mediated by APOL1 variants.

This report describes a patient who underwent cardiac resynchronization complicated by a Twiddler syndrome. This caused triple atrial sensing and an inappropriate shock.

Immediate early response gene X‐1 (IEX‐1) or immediate early response 3 is an immediate early response gene that is highly expressed in epithelial, endothelial, and immune cells, including macrophages.1, 2, 3, 4 Similar to other immediate early response genes, its induction can be rapidly induced in response to several stimuli, such as UV light, inflammatory cytokines, and mechanical strain.4, 5, 6, 7, 8 Under stress, many immediate early response genes, such as c‐Fos, c‐Jun, c‐Myc, Egr‐1, and other zinc‐finger proteins, usually serve as transcription factors, activators, or repressors to regulate the transcriptional activity of several genes that are critical for a cell to appropriately respond to stress.4, 9, 10, 11, 12 However, IEX‐1 lacks a DNA binding domain and its putative transcription activity remains elusive.4, 13 Investigations from our laboratory show that IEX‐1 controls mitochondrial superoxide production by regulating the electron transport chain and oxidative phosphorylation.13, 14, 15, 16 This action of IEX‐1 might explain the transcriptional activity associated with IEX‐1 because the reactive oxygen species (ROS) at low levels can act as a signaling molecule to alter gene transcription through reduction‐oxidation–sensitive transcription factors or a signaling pathway, such as nuclear factor‐κB (NF‐κB) and nuclear factor erythroid 2‐related factor.17, 18, 19 Consistent with a key role of mitochondria in vascular and metabolic functions, IEX‐1 deficiency impairs vascular function and increases energy expenditure in mice. A key role of IEX‐1 in regulation of mitochondrial respiration and ROS production may also help to explain how IEX‐1 produces both antiapoptotic and proapoptotic actions in different cell types. Macrophages, the central player in the pathogenesis of many chronic inflammatory conditions, express high levels of IEX‐1. In agreement with the putative role of IEX‐1 in macrophage function, we recently identified a crucial role of IEX‐1 in many chronic conditions, including hypertension, sepsis, insulin resistance, obesity, and arthritis,16, 20, 21, 22 revealing previously unknown functions of IEX‐1 in cardiovascular and metabolic diseases. In this article, we reviewed the findings in IEX‐1 knockout mice from our laboratory and others and primarily focused on the roles of IEX‐1 in cardiovascular and metabolic disorders. We also alluded to the important findings from other laboratories that are relevant for its role in cardiovascular and metabolic diseases. In addition, an attempt is made to underline the involvement of IEX‐1 in inflammation and its possible link with the lipid‐mediated metabolic diseases. However, because of the limitations and scope of this article, we refrained from discussing an important role of IEX‐1 in many types of cancers that has been widely reported before.

Cardiovascular diseases remain the primary cause of death.1 Myocardial infarction (MI), angina, and stroke take >16 million lives every year, but the underlying mechanisms by which these often‐fatal cardiovascular events occur tend to escape attention.2 Atherosclerosis is the underlying pathological inflammatory vascular disease not only responsible for most MIs and strokes, but it accounts for 29% of deaths worldwide.1, 3 Once believed to be a passive process, it is now understood that atherosclerosis takes an active route involving several cell types, with contributions from a multitude of organ systems, molecular mechanisms, and other pathological conditions, including, but not limited to, hypertension, hyperlipidemia, and type 2 diabetes mellitus.1, 3, 4, 5 Atherosclerosis is characterized by the accumulation of lipids, fibrous elements, and inflammatory cells within the vascular wall of medium and large muscular and elastic arteries.1, 3, 6 Atherosclerotic plaque formation leads to intimal thickening and luminal stenosis.1 Reduction of blood flow ensues, leading to ischemia of the brain, heart, and extremities and clinically manifesting as MI, angina, or stroke. The main features of atherosclerosis are endothelial dysfunction, intimal thickening, inflammation, and vascular calcification (VC).4, 7, 8 These processes are considered a consequence to vascular injury.1 VC is characterized by calcium deposition in the walls of the vasculature.5 Expansion of the calcified lesion leads to thrombus formation and, if significant enough, vascular occlusion. Although the exact mechanisms for VC are unknown, there has been an increase in interest about the role Wingless (Wnt) signaling plays in disease pathogenesis. Briefly, the Wnt signaling pathway is an evolutionarily conserved pathway across kingdom Animalia and plays a crucial role in pattern formation during embryogenesis.9 The Wnt signal transduction pathway plays a crucial role in organ formation in embryonic development, cell proliferation, polarity, migration, and differentiation.10 Thus, deregulated Wnt signaling is associated with many human diseases.11 Therefore, it is justifiable to suggest that research delineating atherogenesis, with focus on the contribution of Wnt signaling in the pathogenesis of atherosclerotic calcification, is warranted.

Aortic valve stenosis due to calcification of the valve leaflets is the most common valve disease in the developed world. It is the third leading cause of cardiovascular disease.1 Risk factors include male gender, smoking, diabetes mellitus, hypertension, high levels of circulating lipids, and metabolic syndrome.2 Calcification was earlier believed to be a passive degenerative process, but it is now recognized as an active disease process driven by the cells native to the aortic valve.3, 4 The only option for treatment is heart surgery with implantation of a valve prosthesis. The heart valve prostheses are either mechanical, requiring life‐long anticoagulation treatment, or based on biological material, which will degenerate and calcify after 10 to 15 years. Implantation of heart valve prostheses has been characterized as “replacing one disease with another.” Understanding the cellular and molecular processes behind valve calcification may possibly lead to nonsurgical treatment. This work was supported by South‐Eastern Norway Regional Health Authority (grant 2013109), the National Association (Norway), the University of Oslo, The Norwegian Research Council, the Government of Russian Federation (grant 074‐U01), and the Russian Foundation of Basic Research (grant 17‐04‐01318).

Thrombin is a key enzyme in hemostasis and thrombosis, regulating pro‐ and anticoagulant reactions by interacting with other coagulation proteins and cellular receptors.[1][1] Thrombin also carries out a plethora of biologically relevant actions that link to other complex biological processes such

In the United States alone, 1 person dies from a coronary event approximately every 1.5 minutes.[1][1] Cardiovascular disease (CVD) encompasses larger subclasses of diseases, such as hypertension, coronary/peripheral artery disease, endothelial dysfunction, and atrial fibrillation, and is

3‐Hydroxy‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors or statins are a class of medications with potent effects on reducing serum cholesterol level, and currently have been widely used in the primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVD).

White matter hyperintensities (WMH) of presumed vascular origin, also referred to as leukoaraiosis, are a very common finding on brain magnetic resonance imaging (MRI) or computed tomography (CT) in older subjects and in patients with stroke and dementia. They are associated with cognitive impairment, triple the risk of stroke and double the risk of dementia. Knowledge of their pathology derives mostly from post mortem studies, many from some years ago. These, by their nature, were generally small, sampled from selected brain regions and probably reflect late‐stage disease. They focus on features of demyelination and axonal degeneration, which may be easier to detect histopathologically than changes in extracellular fluid. Here we review advances in brain magnetic resonance imaging (MRI) that are revealing white matter hyperintensities at earlier stages, and changes in normal‐appearing white matter that indicate tissue pathology, less marked than those found in WMH. These “pre‐visible” changes show that altered interstitial fluid mobility and water content, which may be reversible, probably predate demyelination and axonal damage, which are less likely to be reversible and are probably a late‐stage phenomenon. Neuroimaging is also revealing the dynamic nature of WMH, their interactions with other pathological features such as secondary cortical and long tract damage, and contribution to accumulating brain damage. These insights provide opportunities to improve understanding the etiology and pathogenesis of small vessel disease, and represents an enormous unfinished agenda for preventing accumulation of brain damage, and its associated cognitive and physical problems, from mid to later life. Recognizing the earliest stages leading to WMH development will provide important opportunities to prevent (or even reverse) brain damage due to small vessel disease at the earliest stages, and ameliorate its cognitive, physical, stroke and dementia consequences.

Myocardial ischemia is commonly associated with coronary artery disease as well as many congenital and acquired heart diseases without obstructed coronary arteries. With brief ischemia ventricular function is impaired but myocytes recover, whereas prolonged ischemia causes necrosis and associated

An increasing number of elderly men are receiving exogenous testosterone to treat hypogonadism, low libido, and general weakness.[1][1] The impact of testosterone on the cardiovascular system is controversial. Elderly men are typically at higher risk for adverse cardiovascular events than age

These are exciting times, with a plethora of new technologies that are expediting discovery of the genetic underpinnings of human disease. Comprehensive resequencing of the human genome is now feasible and affordable, allowing each person's entire genetic makeup to be revealed. The major focus of

Hypertension has been defined operationally as the level of blood pressure (BP) at which the benefits of treatment exceed the risks.[1][1] It also has been defined in a more concrete way by the Joint National Committee on Hypertension (JNC-7) as, in adults, a systolic BP ≥140 mm Hg or a diastolic