Showing papers in "Journal of Cardiovascular Translational Research in 2012"

Elastin in large artery stiffness and hypertension

Abstract: Large artery stiffness, as measured by pulse wave velocity, is correlated with high blood pressure and may be a causative factor in essential hypertension. The extracellular matrix components, specifically the mix of elastin and collagen in the vessel wall, determine the passive mechanical properties of the large arteries. Elastin is organized into elastic fibers in the wall during arterial development in a complex process that requires spatial and temporal coordination of numerous proteins. The elastic fibers last the lifetime of the organism but are subject to proteolytic degradation and chemical alterations that change their mechanical properties. This review discusses how alterations in the amount, assembly, organization, or chemical properties of the elastic fibers affect arterial stiffness and blood pressure. Strategies for encouraging or reversing alterations to the elastic fibers are addressed. Methods for determining the efficacy of these strategies, by measuring elastin amounts and arterial stiffness, are summarized. Therapies that have a direct effect on arterial stiffness through alterations to the elastic fibers in the wall may be an effective treatment for essential hypertension.

Arterial Stiffness: Basic Concepts and Measurement Techniques

Abstract: Arterial stiffness is highly relevant to cardiovascular disease. Arterial stiffness is central to the pathogenesis of isolated systolic hypertension and directly impacts left ventricular afterload, pressure pulsatility in the arterial tree, and its penetration into the microvasculature of target organs such as the brain and kidney. Arterial stiffness is affected by various risk factors and biologic processes. Measurements of arterial stiffness may therefore not only provide information about prevalent processes, but also valuable information regarding the cumulative history of risk factor exposure. Available studies consistently demonstrate that large artery stiffness, measured via carotid-femoral pulse wave velocity, independently predicts the risk of incident cardiovascular events in clinical and community-based cohorts. Understanding the basic principles and definitions related to arterial stiffness is therefore desirable for cardiovascular clinicians and researchers. This introductory paper reviews basic physical principles and definitions regarding arterial stiffness and the most important non-invasive methods for its quantification in vivo.

The Actin–MRTF–SRF Gene Regulatory Axis and Myofibroblast Differentiation

Abstract: Cardiac fibroblasts are responsible for necrotic tissue replacement and scar formation after myocardial infarction (MI) and contribute to remodeling in response to pathological stimuli. This response to insult or injury is largely due to the phenotypic plasticity of fibroblasts. When fibroblasts encounter environmental disturbances, whether biomechanical or humoral, they often transform into smooth muscle-like, contractile cells called "myofibroblasts." The signals that control myofibroblast differentiation include the transforming growth factor (TGF)-β1-Smad pathway and Rho GTPase-dependent actin polymerization. Recent evidence implicates serum response factor (SRF) and the myocardin-related transcription factors (MRTFs) as key mediators of the contractile gene program in response to TGF-β1 or RhoA signaling. This review highlights the function of myofibroblasts in cardiac remodeling and the role of the actin-MRTF-SRF signaling axis in regulating this process.

Oxidative Stress, Nox Isoforms and Complications of Diabetes—Potential Targets for Novel Therapies

Abstract: Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy.

The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium.

Abstract: Cardiac fibroblasts are key cellular effectors of cardiac repair; their phenotype and function are modulated by interactions with extracellular matrix proteins. This review manuscript discusses the effects of the extracellular matrix on the inflammatory and reparative properties of fibroblasts in the infarcted myocardium. Early generation of matrix fragments in the infarct induces a pro-inflammatory and matrix-degrading fibroblast phenotype. Formation of a fibrin/fibronectin-rich provisional matrix serves as a conduit for migration of fibroblasts into the infarcted area. Induction of ED-A fibronectin and nonfibrillar collagens may contribute to myofibroblast transdifferentiation. Upregulation of matricellular proteins promotes transduction of growth factor and cytokine-mediated signals. As the scar matures, matrix cross-linking, clearance of matricellular proteins, and reduced growth factor signaling cause deactivation and apoptosis of reparative infarct fibroblasts. Understanding the effects of matrix components on infarct fibroblasts may guide the design of peptides that reproduce, or inhibit, specific matricellular functions, attenuating adverse remodeling.

MicroRNAs and diabetic complications.

Abstract: Both Type 1 and Type 2 diabetes can lead to debilitating microvascular complications such as retinopathy, nephropathy and neuropathy, as well as macrovascular complications such as cardiovascular diseases including atherosclerosis and hypertension. Diabetic complications have been attributed to several contributing factors such as hyperglycemia, hyperlipidemia, advanced glycation end products, growth factors, and inflammatory cytokines/chemokines. However, current therapies are not fully efficacious and hence there is an imperative need for a better understanding of the molecular mechanisms underlying diabetic complications in order to identify newer therapeutic targets. microRNAs (miRNAs) are short non-coding RNAs that repress target gene expression via post-transcriptional mechanisms. Emerging evidence shows that they have diverse cellular and biological functions and play key roles in several diseases. In this review, we explore the role of miRNAs in the pathology of diabetic complications and also discuss the potential use of miRNAs as novel diagnostic and therapeutic targets for diabetic complications.

What Do We Know and We Do Not Know About Cardiovascular Autonomic Neuropathy in Diabetes

Abstract: Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems’ tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.

Extracellular matrix and fibroblast communication following myocardial infarction.

Abstract: The extracellular matrix (ECM) provides structural support by serving as a scaffold for cells, and as such the ECM maintains normal tissue homeostasis and mediates the repair response following injury. In response to myocardial infarction (MI), ECM expression is generally upregulated in the left ventricle (LV), which regulates LV remodeling by modulating scar formation. The ECM directly affects scar formation by regulating growth factor release and cell adhesion and indirectly affects scar formation by regulating the inflammatory, angiogenic, and fibroblast responses. This review summarizes the current literature on ECM expression patterns and fibroblast mechanisms in the myocardium, focusing on the ECM response to MI. In addition, we discuss future research areas that are needed to better understand the molecular mechanisms of ECM action, both in general and as a means to optimize infarct healing.

The Vascular Stem Cell Niche

Abstract: Stem cells in adult organs reside in specialized niches that regulate their proliferation and differentiation. Investigations during the last few years have unveiled a regulatory role for blood vessels in these microenvironments. Mesenchymal stem cells (MSCs) are located surrounding capillaries in a variety of tissues and have the capacity to differentiate into different mesodermal lineages. Angiogenic progenitor cells have also been found in the adventitial layer of large vessels. In the bone marrow, endothelial cells control hematopoietic stem cell (HSC) release, and in the brain, blood vessels regulate neural stem cell (NSC) self-renewal and neurogenesis. Similarly, perivascular progenitor cells have also been found in the heart. This intimate connection between stem cells and the vasculature contributes to tissue homeostasis and repair. In this review, we focus on the regulation of stem and progenitor cells in different adult niches by blood vessels and the few mechanisms that are known to mediate this interaction.

Diabetic complications: current challenges and opportunities

Abstract: The International Diabetes Federation estimates that 366 million people had diabetes in 2011, and that by 2030, this figure will have risen to a staggering 552 million worldwide. In 2011, diabetes was the cause of 4.6 million deaths and accounted for 11 % of adult healthcare expenditure in the USA [1]. The increasing incidence of both type 1 diabetes (T1D) and type 2 diabetes (T2D) elevates the complications of diabetes as one of the most important current public health issues. Complications of diabetes range from acute, life-threatening conditions such as severe hypoglycemia or ketoacidosis to chronic, debilitating complications affecting multiple organ systems, such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. Estimates of the prevalence of diabetic complications are challenging, in part because there are no internationally agreed upon standards for diagnosis. However, a vast majority of those with diabetes will experience one of more of these complications of diabetes. For example, a recent analysis by the META-EYE study group reported that 93 million people worldwide suffer from diabetic retinopathy. For those with 20 or more years of diabetes, three quarters have some form of diabetic retinopathy [2].

Electrical and mechanical ventricular activation during left bundle branch block and resynchronization.

Abstract: Cardiac resynchronization therapy (CRT) aims to treat selected heart failure patients suffering from conduction abnormalities with left bundle branch block (LBBB) as the culprit disease. LBBB remained largely underinvestigated until it became apparent that the amount of response to CRT was heterogeneous and that the therapy and underlying pathology were thus incompletely understood. In this review, current knowledge concerning activation in LBBB and during biventricular pacing will be explored and applied to current CRT practice, highlighting novel ways to better measure and treat the electrical substrate.

Cardiovascular Disease Risk in Young People with Type 1 Diabetes

Abstract: Cardiovascular disease (CVD) is the most frequent cause of death in people with type 1 diabetes (T1D), despite modern advances in glycemic control and CVD risk factor modification. CVD risk identification is essential in this high-risk population, yet remains poorly understood. This review discusses the risk factors for CVD in young people with T1D, including hyperglycemia, traditional CVD risk factors (dyslipidemia, smoking, physical activity, hypertension), as well as novel risk factors such as insulin resistance, inflammation, and hypoglycemia. We present evidence that adverse changes in cardiovascular function, arterial compliance, and atherosclerosis are present even during adolescence in people with T1D, highlighting the need for earlier intervention. The methods for investigating cardiovascular risk are discussed and reviewed. Finally, we discuss the observational studies and clinical trials which have thus far attempted to elucidate the best targets for early intervention in order to reduce the burden of CVD in people with T1D.

The Hypoxic Epicardial and Subepicardial Microenvironment

Abstract: Recent reports indicate that the adult mammalian heart is capable of limited, but measurable, cardiomyocyte turnover. While the lineage origin of the newly formed cardiomyocytes is not entirely understood, mounting evidence suggest that the epicardium and subepicardium may represent an important source of cardiac stem or progenitor cells. Stem cell niches are characterized by low oxygen tension, where stem cells preferentially utilize cytoplasmic glycolysis to meet their energy demands. However, it is unclear if the heart harbors similar hypoxic regions, or whether these regions house metabolically distinct cardiac progenitor populations. Here we identify the epicardium and subepicardium as the cardiac hypoxic niche-based capillary density quantification, and localization of Hif-1α in the uninjured heart. We further demonstrate that this hypoxic microenvironment houses a metabolically distinct population of glycolytic progenitor cells. Finally, we show that Hif-1α regulates the glycolytic phenotype and progenitor properties of these cells. These findings highlight important anatomical and functional properties of the epicardial and subepicardial microenvironment, and the potential role of hypoxia signaling in regulation of cardiac progenitors.

Cell Delivery Routes for Stem Cell Therapy to the Heart: Current and Future Approaches

Abstract: An important factor to determine the success of stem cell therapy to the heart is the choice of cell delivery route. This will affect the fate of donor cells and subsequently influence the outcome of treatment; however, there is currently no optimum cell delivery route appropriate for every disease condition or every donor cell type. This review summarises currently available approaches for administering cells to the heart, with a particular focus on cell retention/survival and the therapeutic benefits seen in preclinical and clinical studies. Two major approaches are intracoronary and intramyocardial injection, which have been widely used for the delivery of various types of cells. Although there are advantages to both approaches, donor cell retention and survival are poor using these methods, potentially limiting therapeutic effects. Various attempts to improve current approaches, along with the development of emerging new approaches, are also described and discussed in this review.

Cardiac intercellular communication: are myocytes and fibroblasts fair-weather friends?

Abstract: The cardiac fibroblast (CF) has historically been thought of as a quiescent cell of the heart, passively maintaining the extracellular environment for the cardiomyocytes (CM), the functional cardiac cell type. The increasingly appreciated role of the CF, however, extends well beyond matrix production, governing many aspects of cardiac function including cardiac electrophysiology and contractility. Importantly, its contributions to cardiac pathophysiology and pathologic remodeling have created a shift in the field's focus from the CM to the CF as a therapeutic target in the treatment of cardiac diseases. In response to cardiac injury, the CF undergoes a pathologic phenotypic transition into a myofibroblast, characterized by contractile smooth muscle proteins and upregulation of collagens, matrix proteins, and adhesion molecules. Further, the myofibroblast upregulates expression and secretion of a variety of pro-inflammatory, profibrotic mediators, including cytokines, chemokines, and growth factors. These mediators act in both an autocrine fashion to further activate CFs, as well as in a paracrine manner on both CMs and circulating inflammatory cells to induce myocyte dysfunction and chronic inflammation, respectively. Together, cell-specific cytokine-induced effects exacerbate pathologic remodeling and progression to HF. A better understanding of this dynamic intercellular communication will lead to novel targets for the attenuation of cardiac remodeling. Current strategies aimed at targeting cytokines have been largely unsuccessful in clinical trials, lending insights into ways that such intercellular cross talk can be more effectively attenuated. This review will summarize the current knowledge regarding CF functions in the heart and will discuss the regulation and signaling behind CF-mediated cytokine production and function. We will then highlight clinical trials that have exploited cytokine cross talk in the treatment of heart failure and provide novel strategies currently under investigation that may more effectively target pathologic CF-CM communication for the treatment of cardiac disease. This review explores novel mechanisms to directly attenuate heart failure progression through inhibition of signaling downstream of pro-inflammatory cytokines that are elevated after cardiac injury.

Haptoglobin genotype and its role in diabetic cardiovascular disease.

Abstract: Over the past decade, several longitudinal epidemiological studies have brought attention to the haptoglobin genotype and its importance in determining diabetic vascular disease risk. This manuscript presents an overview of the biology of the haptoglobin genotype and reviews the literature concerning its role in the development of cardiovascular disease among individuals with diabetes mellitus.

Origin of Developmental Precursors Dictates the Pathophysiologic Role of Cardiac Fibroblasts

Abstract: Fibroblasts in the heart play a critical function in the secretion and modulation of extracellular matrix critical for optimal cellular architecture and mechanical stability required for its mechanical function. Fibroblasts are also intimately involved in both adaptive and nonadaptive responses to cardiac injury. Fibroblasts provide the elaboration of extracellular matrix and, as myofibroblasts, are responsible for cross-linking this matrix to form a mechanically stable scar after myocardial infarction. By contrast, during heart failure, fibroblasts secrete extracellular matrix, which manifests itself as excessive interstitial fibrosis that may mechanically limit cardiac function and distort cardiac architecture (adverse remodeling). This review examines the hypothesis that fibroblasts mediating scar formation and fibroblasts mediating interstitial fibrosis arise from different cellular precursors and in response to different autocoidal signaling cascades. We demonstrate that fibroblasts which generate scars arise from endogenous mesenchymal stem cells, whereas those mediating adverse remodeling are of myeloid origin and represent immunoinflammatory dysregulation.

The dynamic role of cardiac fibroblasts in development and disease.

Abstract: Cardiac fibroblasts are the most abundant cell in the mammalian heart. While they have been historically overlooked in terms of functional contributions to development and physiology, cardiac fibroblasts are now front and center. They are currently recognized as key protagonists during both normal development and cardiomyopathy disease, and work together with cardiomyocytes through paracrine, structural, and potentially electrical interactions. However, the lack of specific biomarkers and fibroblast heterogeneous nature currently convolutes the study of this dynamic cell lineage; though, efforts to advance marker analysis and lineage mapping technologies are ongoing. These tools will help elucidate the functional significance of fibroblast-cardiomyocyte interactions in vivo and delineate the dynamic nature of normal and pathological cardiac fibroblasts. Since therapeutic promise lies in understanding the interface between developmental biology and the postnatal injury response, future studies to understand the divergent roles played by cardiac fibroblasts both in utero and following cardiac insult are essential.

Mathematical Modeling and Simulation of Ventricular Activation Sequences: Implications for Cardiac Resynchronization Therapy

Abstract: Next to clinical and experimental research, mathematical modeling plays a crucial role in medicine. Biomedical research takes place on many different levels, from molecules to the whole organism. Due to the complexity of biological systems, the interactions between components are often difficult or impossible to understand without the help of mathematical models. Mathematical models of cardiac electrophysiology have made a tremendous progress since the first numerical ECG simulations in the 1960s. This paper briefly reviews the development of this field and discusses some example cases where models have helped us forward, emphasizing applications that are relevant for the study of heart failure and cardiac resynchronization therapy.

Epicardial Progenitor Cells in Cardiac Development and Regeneration

Abstract: The epicardium forms an epithelial layer on the surface of the heart. It is derived from a cluster of mesothelial cells, which is termed the proepicardium. The proepicardium gives rise not only to the epicardium but also to epicardium-derived cells. These cells populate the myocardial wall and differentiate into smooth muscle cells, fibroblast, and possibly endothelial cells. In this review, the formation of the proepicardium is discussed. Marker genes, suitable to identify these cells in the embryo and in the adult, are introduced. Recent evidence suggests that the PE is made up of distinct cell populations. These cell lineages can be distinguished on the basis of marker gene expression and differ in their differentiation potential. The role of the epicardium as a resource for cardiac stem cells and its importance in cardiac regeneration is also discussed.

Crosstalk Between the Renin–Angiotensin System and the Advance Glycation End Product Axis in the Heart: Role of the Cardiac Fibroblast

Abstract: Cardiac fibroblasts (CFs) are involved in maintaining extracellular matrix (ECM) homeostasis in the heart. CFs mediate responses to hormonal and mechanical stimuli and relay these to other local cell types through release of autocrine and/or paracrine factors. CFs also play important roles in the setting of injury, i.e., myocardial infarction, where ECM production is key to efficient scarring. However, conditions exist in which excess production of ECM by CFs can lead to cardiac fibrosis. Two important pathways known to be involved in development of cardiac fibrosis are renin–angiotensin system (RAS) and advanced glycation end products (AGE) receptor (RAGE) signaling cascades. This report summarizes actions of these two pathways on function of CFs. Because cardiac fibrosis is an important component of diabetic cardiomyopathy, we include new data that suggests a possible crosstalk between the RAS and AGE/RAGE pathway in order to activate CFs in diabetes.

Chromatin modifications associated with diabetes

Abstract: Accelerated rates of vascular complications are associated with diabetes mellitus. Environmental factors including hyperglycaemia contribute to the progression of diabetic complications. Epidemiological and experimental animal studies identified poor glycaemic control as a major contributor to the development of complications. These studies suggest that early exposure to hyperglycaemia can instigate the development of complications that present later in the progression of the disease, despite improved glycaemic control. Recent experiments reveal a striking commonality associated with gene-activating hyperglycaemic events and chromatin modification. The best characterised to date are associated with the chemical changes of amino-terminal tails of histone H3. Enzymes that write specified histone tail modifications are not well understood in models of hyperglycaemia and metabolic memory as well as human diabetes. The best-characterised enzyme is the lysine specific Set7 methyltransferase. The contribution of Set7 to the aetiology of diabetic complications may extend to other transcriptional events through methylation of non-histone substrates.

Left Bundle Branch Block, an Old–New Entity

Abstract: Left bundle branch block (LBBB) is generally associated with a poorer prognosis in comparison to normal intraventricular conduction, but also in comparison to right bundle branch block which is generally considered to be benign in the absence of an underlying cardiac disorder like congenital heart disease. LBBB may be the first manifestation of a more diffuse myocardial disease. The typical surface ECG feature of LBBB is a prolongation of QRS above 0.11 s in combination with a delay of the intrinsic deflection in leads V5 and V6 of more than 60 ms and no septal q waves in leads I, V5, and V6 due to the abnormal septal activation from right to left. LBBB may induce abnormalities in left ventricular performance due to abnormal asynchronous contraction patterns which can be compensated by biventricular pacing (resynchronization therapy). Asynchronous electrical activation of the ventricles causes regional differences in workload which may lead to asymmetric hypertrophy and left ventricular dilatation, especially due to increased wall mass in late-activated regions, which may aggravate preexisting left ventricular pumping performance or even induce it. Of special interest are patients with LBBB and normal left ventricular dimensions and normal ejection fraction at rest but who may present with an abnormal increase in pulmonary artery pressure during exercise, production of lactate during high-rate pacing, signs of ischemia on myocardial scintigrams (but no coronary artery narrowing), and abnormal ultrastructural findings on myocardial biopsy. For this entity, the term latent cardiomyopathy had been suggested previously.

Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes

Abstract: Follistatins are extracellular inhibitors of the TGF-β family ligands including activin A, myostatin and bone morphogenetic proteins. Follistatin-like 3 (FSTL3) is a potent inhibitor of activin signalling and antagonises the cardioprotective role of activin A in the heart. FSTL3 expression is elevated in patients with heart failure and is upregulated in cardiomyocytes by hypertrophic stimuli, but its role in cardiac remodelling is largely unknown. Here, we show that the production of FSTL3 by cardiomyocytes contributes to the paracrine activation of cardiac fibroblasts, inducing changes in cell adhesion, promoting proliferation and increasing collagen production. We found that FSTL3 is necessary for this response and for the induction of cardiac fibrosis. However, full activation requires additional factors, and we identify connective tissue growth factor as a FSTL3 binding partner in this process. Together, our data unveil a novel mechanism of paracrine communication between cardiomyocytes and fibroblasts that may provide potential as a therapeutic target in heart remodelling.

Optimizing cardiac repair and regeneration through activation of the endogenous cardiac stem cell compartment

Abstract: Given the aging of the Western World and declining death rates due to acute coronary syndromes, the increasing trends in the magnitude and morbidity of heart failure (HF) are predicted to continue for the foreseeable future. It is imperative to develop effective therapies for the amelioration and prevention of HF. The search for the best cell type to be used in clinical protocols of cardiac regeneration is still on. That the adult mammalian heart harbors endogenous, multipotent cardiac stem/progenitor cells (eCSCs) and that cardiomyocytes are replaced throughout adulthood represent a paradigm shift in cardiovascular biology. The presence of eCSCs supports the view that the heart can repair itself if the eCSCs can be properly stimulated. Pending a better understanding of eCSC biology, it should be possible to replace autologous cell transplantation-based myocardial regeneration protocols with an “off-the-shelf,” readily available, and effective regenerative/reparative therapy based on activation of the eCSCs in situ.

Development of High Content Imaging Methods for Cell Death Detection in Human Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) are being investigated as a new source of cardiac cells for drug safety assessment. We developed a novel scalable high content microscopy-based method for the detection of cell death in hPSC-CM that can serve for future predictive in vitro cardio-toxicological screens. Using rat neonatal ventricular cardiomyocytes (RVNC) or hPSC-CM, assays for nuclear remodelling, mitochondrial status, apoptosis and necrosis were designed using a combination of fluorescent dyes and antibodies on an automated microscopy platform. This allowed the observation of a chelerythrine-induced concentration-dependent apoptosis to necrosis switch and time-dependent progression of early apoptotic cells towards a necrotic-like phenotype. Susceptibility of hPSC-CM to chelerythrine-stimulated apoptosis varied with time after differentiation, but at most time points, hPSC-CM were more resistant than RVNC. This simple and scalable humanized high-content assay generates accurate cardiotoxicity profiles that can serve as a base for further assessment of cardioprotective strategies and drug safety.

Perspectives on Systems Biology Applications in Diabetic Kidney Disease

Abstract: Diabetic kidney disease (DKD) is a microvascular complication of type 1 and 2 diabetes with a devastating impact on individuals with the disease, their families, and society as a whole. DKD is the single most frequent cause of incident chronic kidney disease cases and accounts for over 40 % of the population with end-stage renal disease. Contributing factors for the high prevalence are the increase in obesity and subsequent diabetes combined with an improved long-term survival with diabetes. Environment and genetic variations contribute to DKD susceptibility and progressive loss of kidney function. How the molecular mechanisms of genetic and environmental exposures interact during DKD initiation and progression is the focus of ongoing research efforts. The development of standardized, unbiased high-throughput profiling technologies of human DKD samples opens new avenues in capturing the multiple layers of DKD pathobiology. These techniques routinely interrogate analytes on a genome-wide scale generating comprehensive DKD-associated fingerprints. Linking the molecular fingerprints to deep clinical phenotypes may ultimately elucidate the intricate molecular interplay in a disease stage and subtype-specific manner. This insight will form the basis for accurate prognosis and facilitate targeted therapeutic interventions. In this review, we present ongoing efforts from large-scale data integration translating “-omics” research efforts into improved and individualized health care in DKD.

The Origin and Arrhythmogenic Potential of Fibroblasts in Cardiac Disease

Abstract: Fibroblasts play a major role in normal cardiac physiology and in the response of the heart to injury and disease. Cardiac electrophysiological research has primarily focused on the mechanisms of remodeling that accompany cardiac disease with an emphasis on myocyte electrophysiology. Recently, there has been increasing interest in the potential role of fibroblasts in cardiac electrophysiology. This review focuses on the arrhythmia mechanisms involving interactions between myocytes and fibroblasts. We also discuss the available evidence supporting the contribution of intracardiac and extracardiac sources to the fibroblast and myofibroblast populations in diseased hearts.

Animal models of dyssynchrony

Abstract: Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT.

Translational lessons from a case of combined heart and liver transplantation for familial hypercholesterolemia 20 years post-operatively.

Abstract: We review the lessons from a case of combined heart and liver transplantation (CHLT) 20 years post-operatively from the molecular to clinical levels. CHLT replaces cardiac function and provides a new source of Low density lipoprotein–receptors (LDL-R) known to be deficient in Familial Hypercholesterolaemia. Little is known of the long-term outcomes of this strategy. We review the lessons from a case of CHLT 20 years post-operatively, which illustrate the successful transition from the molecular understanding of the pathophysiology to the clinical therapy. Most importantly, there is evidence that transplantation of multiple organs from a single donor promotes operational tolerance, especially in the case of the liver. This lady presented in severe heart failure with advanced atherosclerotic disease resulting in coronary artery and aortic valve stenosis. The serum LDL-C concentration of 13 mmol/L was refractory to conventional therapy. Genetic analysis showed a large deletion on one allele of the LDL-R, and a mutant allele that produced a receptor which was delayed in its transport to the cell membrane and had 10% of normal receptor activity. The patient had a normalised lipid-profile directly after CHLT (2.1 mmol/L), and this has remained stable since the time of operation. Apart from a minor episode of cardiac rejection at 3 weeks post-CHLT, the patient has had excellent heart and liver function throughout. This patient has not experienced any signs of rejection, despite only low-dose immunosuppression. We review what we have learnt from this case at the molecular and clinical levels.