Cardiac Syndrome X; Microvascular Coronary Dysfunction
The importance of endothelial dysfunction in the development and clinical expression of cardiovascular disease is well recognized. Impaired endothelial function has been associated with an increased risk of cardiovascular events. Endothelial function may be evaluated in humans by assessing vasodilation in response to stimuli known to induce the release of nitric oxide. A novel pulse amplitude tonometry device noninvasively measures vasodilator function in the microcirculation of the finger. This article reviews the recent studies that support the utility of digital pulse amplitude tonometry as a relevant test of peripheral endothelial function.
The transcriptional co-activators PGC-1α and PGC-1β are master regulators of oxidative phosphorylation and fatty acid oxidation gene expression. Pressure overload hypertrophy and heart failure are associated with repressed PGC-1α and PGC-1β gene expression. Maintaining expression of PGC-1α and β preserves contractile function in response to a pathological increase in workload. Here we discuss the regulation of PGC-1 proteins under conditions of pressure overload hypertrophy and heart failure.
In normal and diseased vascular smooth muscle (SM), the RhoA pathway, which is activated by multiple agonists through G protein-coupled receptors (GPCRs), plays a central role in regulating basal tone and peripheral resistance. Multiple RhoA GTP exchange factors (GEFs) are expressed in SM raising the possibility that specific agonists coupled to specific GPCRs may couple to distinct RhoGEFs and provide novel therapeutic targets. This review will focus on the function and mechanisms of activation of p63RhoGEF (Arhgef 25; GEFT) recently identified in SM and its possible role in selective targeting of RhoA-mediated regulation of basal blood pressure through agonists that couple through Gαq/11.
For more than a half century, autoimmunity has been linked to a diverse array of heart diseases including rheumatic carditis, myocarditis, Chagas’ cardiomyopathy, post-myocardial infarction (Dressler’s) syndrome, and idiopathic dilated cardiomyopathy. Why the heart is targeted by autoimmunity in these seemingly unrelated conditions has remained enigmatic. Here, we discuss our recent studies indicating that this susceptibility is mediated by impaired negative selection of autoreactive α-myosin heavy chain -specific CD4+ T cells in the thymus of both mice and humans. We describe how this process may place the heart at increased risk for autoimmune attack following ischemic or infectious injury, providing a rationale for the development of antigen-specific tolerogenic therapies.
Mast cells (MCs) are implicated in the pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA). MC-specific chymase and tryptase play important roles in inducing endothelial cell expression of adhesion molecules and chemokines to promote leukocyte recruitment, degrading matrix proteins and activating protease-activated receptors to trigger smooth-muscle cell apoptosis, and activating other proteases to degrade medial elastin and to enhance angiogenesis. In experimental AAA, absence or pharmacological inhibition of chymase or tryptase reduced AAA formation and associated arterial pathologies, proving that these MC proteases participate directly in AAA formation. Increased levels of these proteases in human AAA lesions and in plasma from AAA patients suggest that these proteases are also essential to human AAA pathogenesis. Development of chymase or tryptase inhibitors or their antibodies may have therapeutic potential among affected human subjects.
The association between low exercise capacity and all-cause morbidity and mortality is statistically strong yet mechanistically unresolved. By connecting clinical observation with a theoretical base, we developed a working hypothesis that variation in capacity for oxygen metabolism is the central mechanistic determinant between disease and health (aerobic hypothesis). As an unbiased test, we show that two-way artificial selective breeding of rats for low and high intrinsic endurance exercise capacity also produces rats that differ for numerous disease risks including the metabolic syndrome, cardiovascular complications, premature aging, and reduced longevity. This contrasting animal model system may prove to be translationally superior, relative to more widely-used simplistic models for understanding geriatric biology and medicine.
Over the past hundred years, the fruit fly, Drosophila melanogaster, has provided tremendous insights into genetics and human biology. Drosophila-based research utilizes powerful, genetically-tractable approaches to identify new genes and pathways that potentially contribute to human diseases. New resources available in the fly research community have advanced the ability to examine genome-wide effects on cardiac function and facilitate the identification of structural, contractile, and signaling molecules that contribute to cardiomyopathies. This powerful model system continues to provide discoveries of novel genes and signaling pathways that are conserved among species and translatable to human pathophysiology.
Rapamycin is an FDA approved drug for the prevention of immunorejection following organ transplantation. Pharmacological studies suggest a potential new application of rapamycin in attenuating cardiomyopathy, but the potential for this application is not yet supported by genetic studies of genes in target of rapamycin (TOR) signaling in rodents. Recently, supporting genetic evidence was presented in zebrafish using two adult cardiomyopathy models. By characterizing a heterozygous zebrafish target of rapamycin (ztor) mutant, the therapeutic effect of long-term TOR signaling inhibition was demonstrated. Dose- and stage-dependent functions of TOR signaling provide an explanation for the seemingly contradictory results obtained in genetic studies of TOR components in rodents. The results from the zebrafish studies, together with the supporting preliminary clinical studies, suggested that TOR signaling inhibition should be further pursued as a novel therapeutic strategy for cardiomyopathy. Future directions for developing TOR-based therapy include assessing the long-term benefits of rapamycin as a candidate drug for heart failure patients, defining the dynamic activity of TOR, exploring the impacts of TOR signaling manipulation in different models of cardiomyopathies, and elucidating the downstream signaling branches that confer the therapeutic effects of TOR signaling inhibition.
Pannexins are a recently discovered protein family, with the isoform Panx1 ubiquitously expressed and therefore extensively studied. Panx1 proteins form membrane channels known to release purines such as ATP. Because ATP and more generally purinergic signaling plays an important role in the vasculature, it became evident that Panx1 could have a key role in vascular functions. This article review deals with recent findings on the pivotal role of Panx1 in smooth muscle cells in the contraction of arteries as well as recent insights in Panx1 channel regulation.
Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification.
vascular smooth muscle; calcification; S100/calgranulin
Stem cell therapies promise to regenerate the infarcted heart through the replacement of dead cardiac cells and stimulation of neovascularization. New research from our laboratory shows the transplantation of stem cells from human veins helps heart healing after an acute ischemic insult. Using a mouse model, we demonstrated that pericytes expanded from redundant human leg veins relocate around the vessels of the peri-infarct zone and release factors that promote reparative angiogenesis and cardiomyocyte survival and inhibit interstitial fibrosis. We plan to perform a first-in-man clinical trial with human pericytes in patients with refractory myocardial ischemia in the next 5 years.
Over the past 2 decades, stem cells have created enthusiasm as a regenerative therapy for ischemic heart disease (IHD). Transplantation of bone marrow stem cells, skeletal myoblasts, and endothelial progenitor cells has shown to improve myocardial function after infarction. More recently, attention has focused on the potential use of embryonic stem cells (ESC) and induced pluripotent stem cells (iPS), as they possess the capacity to differentiate into various cell types, including cardiac and endothelial cells. Clinical trials have shown positive effects on the functional recovery of heart after myocardial infarction (MI) and have answered questions on timing, dosage, and cell delivery route of stem cells such as those derived from bone marrow. Despite the current advances in stem cell research, one main hurdle remains the lack of reliable information about the fate of cell engraftment, survival, and proliferation after transplantation. This review will discuss the different cell types used in cardiac cell therapy as well as molecular imaging modalities relevant to survival issues.
In mouse heart, four connexins (Cxs), Cx30.2, Cx40, Cx43, and Cx45, form gap junction (GJ) channels for electric and metabolic cell-to-cell signaling. Extent and pattern of Cx isoform expression together with cytoarchitecture and excitability of cells determine the velocity of excitation spread in different regions of the heart. In the SA node, cell– cell coupling is mediated by Cx30.2 and Cx45, which form lowconductance (approximately 9 and 32 pS, respectively) GJ channels. In contrast, the working cardiomyocytes of atria and ventricles express mainly Cx40 and Cx43, which form GJ channels of high conductance (approximately 180 and 115 pS, respectively) that facilitate the fast conduction necessary for efficient mechanical contraction. In the AV node, cell–cell coupling is mediated by abundantly expressed Cx30.2 and Cx45 and Cx40, which is expressed to a lesser extent. Cx30.2 and Cx45 may determine higher intercellular resistance and slower conduction in the SA- and AV-nodal regions than in the ventricular conduction system or the atrial and ventricular working myocardium. Cx30.2 and its putative human ortholog, Cx31.9, under physiologic conditions form unapposed hemichannels in nonjunctional plasma membrane; these hemichannels have a conductance of approximately 20 pS and are permeable to cationic dyes up to approximately 400 Da in molecular mass. Genetic ablation of Cxs confirmed that Cx40 and Cx43 are important in determining the high conduction velocities in atria and ventricles, whereas the deletion of the Cx30.2 complementary DNA led to accelerated conduction in the AV node and reduced the Wenckebach period. We suggest that these effects are caused by (1) a dominant-negative effect of Cx30.2 on junctional conductance via formation of low-conductance homotypic and heterotypic GJ channels, and (2) open Cx30.2 hemichannels in non-junctional membranes, which shorten the space constant and depolarize the excitable membrane.
Intercalated disks (ICDs) are highly organized cell-cell adhesion structures, which connect cardiomyocytes to one another. They are composed of three major complexes: desmosomes, fascia adherens, and gap junctions. Desmosomes and fascia adherens junction are necessary for mechanically coupling and reinforcing cardiomyocytes, whereas gap junctions are essential for rapid electrical transmission between cells. Because human genetics and mouse models have revealed that mutations and/or deficiencies in various ICD components can lead to cardiomyopathies and arrhythmias, considerable attention has focused on the biologic function of the ICD. This review will discuss recent scientific developments related to the ICD and focus on its role in regulating cardiac muscle structure, signaling, and disease.
The possibility of using stem cells to regenerate damaged myocardium has been actively investigated since the late 1990s. Consistent with the traditional view that the heart is a “post-mitotic” organ that possesses minimal capacity for self-repair, much of the preclinical and clinical work has focused exclusively on introducing stem cells into the heart, with the hope of differentiation of these cells into functioning cardiomyocytes. This approach is ongoing and retains promise but to date has yielded inconsistent successes. More recently, it has become widely appreciated that the heart possesses endogenous repair mechanisms that, if adequately stimulated, might regenerate damaged cardiac tissue from in situ cardiac stem cells. Accordingly, much recent work has focused on engaging and enhancing endogenous cardiac repair mechanisms. This article reviews the literature on stem-cell based myocardial regeneration, placing emphasis on the mutually enriching interaction between basic and clinical research.
regeneration; stem cell; infarction; myocardium
Congenital heart diseases associated with increased pulmonary blood flow commonly lead to the development of pulmonary hypertension. However, most patients who undergo histological evaluation have advanced pulmonary hypertension, and therefore it has been difficult to investigate aberrations in signaling cascades that precede the development of overt vascular remodeling. The purpose of this review is to discuss the role played by oxidative and nitrosative stress in the lung and their impact on the signaling pathways that regulate vasodilation, vessel growth and vascular remodeling in the neonatal lung exposed to increased pulmonary blood flow.
During the early weeks of human gestation, hematopoietic cells first emerge within the extraembryonic yolk sac (primitive hematopoiesis) and secondarily within the truncal arteries of the embryo. This second wave includes the stem cells giving rise to adult-type lymphohematopoiesis. In both yolk sac blood islands and embryonic aorta, hematopoietic cells arise in the immediate vicinity of vascular endothelial cells. In vitro hematopoietic differentiation of endothelial cells stringently sorted from human embryonic and fetal blood-forming tissues has demonstrated that primitive endothelium lies at the origin of incipient hematopoiesis. These anatomically and temporally localized blood-forming endothelial cells are ultimately derived from a rare subset of mesodermal angio-hematopoietic stem cells, or hemangioblasts. The evidence for an early progenitor of blood-forming cells within the walls of human embryonic blood vessels concurs with parallel data obtained from lower vertebrate, avian, and murine models. Importantly, converging results have recently been obtained with in vitro differentiated human embryonic stem cells, in which we have modeled primitive and definitive hematopoiesis via an endothelium-like developmental intermediate.
Graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, Is characterized by a diffuse, concentric arterial intimal hyperplasia composed of infiltrating host T cells, macrophages and predominantly graft-derived smooth muscle–like cells that proliferate and elaborate extracellular matrix, resulting in luminal obstruction and allograft ischemia. IFN-γ, a proinflammatory cytokine produced by effector T cells, is a critical mediator for smooth muscle – like cell proliferation. We have exploited the power of mouse genetics to examine the function of AIP1, a signaling adaptor molecule involved in vascular inflammation, in two newly established IFN-γ-mediated models of GA. Our data suggest that AIP1 inhibits intimal formation in GA by downregulating IFN-γ–activated migratory and proliferative signaling pathways in smooth muscle–like cells.
As exemplified by desmin-related cardiomyopathy and myocardial ischemia/reperfusion injury, proteasome functional insufficiency plays an essential pathogenic role in the progression of cardiac diseases with elevated proteotoxic stress. Upregulation of p62/SQSTM1 and increased selective autophagy in cardiomyocytes may protect against proteotoxic stress in the heart. p62 may serve as a proteotoxic stress sensor, promote segregation and degradation of misfolded proteins by autophagy, and mediate the crosstalk between the ubiquitin-proteasome system and autophagy.
In response to injury the myocardium hypertrophies in an attempt to maintain or augment function, which is associated with ventricular remodeling and changes in capillary density. During the compensatory phase of the hypertrophic response the myocardium maintains output and is characterized by a coordinated neo-angiogenic and fibrotic response that supports cardiomyocyte health and survival. Emerging evidence shows that paracrine-mediated cross-talk between cardiac myocytes and non-myocytes within the heart is critical for cardiac adaptation to stress, including the extent of hypertrophy and angiogenesis. This review will discuss recent results indicating that Placental Growth Factor (PGF, also called PlGF), a secreted factor within the VEGF superfamily, is a pivotal mediator of adaptive cardiac hypertrophy and beneficial angiogenesis through its ability to coordinate the intercellular communication between different celltypes in the heart.
The four fibroblast growth factor homologous factors (FHFs, FGF11–FGF14) are intracellular proteins that bind and modulate voltage-gated sodium channels (VGSCs). While FHFs have been well studied in neurons and implicated in neurologic disease, their role in cardiomyocytes was unclear until recently. In this review, we discuss the expression profile and function of FHFs in mouse and rat ventricular cardiomyocytes. Recent data show that FGF13 is the predominant FHF in the murine heart, directly binds the cardiac VGSC α subunit, and is essential for normal cardiac conduction. FHF loss-of-function mutations may be unrecognized causes of cardiac arrhythmias, such as Long QT and Brugada syndromes.
Pulmonary hypertension (PH) is a disease of high lethality arising from numerous causes. For a significant subset of PH patients, autoimmune biomarkers or frank autoimmune disease are simultaneously present, but the extent to which lung inflammation contributes to PH is currently unknown. However, emerging experimental and clinical evidence suggests that immune dysregulation may lead to the propagation of vascular injury and PH. A recent preclinical study has demonstrated that regulatory T cells (Tregs) are important mediators normally enlisted to control inflammation and that, if absent or dysfunctional, may predispose to the development of PH.
Atherosclerosis is a complex vascular pathology characterized in part by accumulation of innate and adaptive inflammatory cells in arterial plaque. Molecular mediators responsible for inflammatory cell accumulation in plaque include specific members of the chemokine family of leukocyte chemoattractants and their G protein-coupled receptors. Studies using the ApoE knockout mouse model have recently implicated chemokine receptor Ccr6 and its ligand Ccl20 as a non-redundant ligand-receptor pair in atherosclerosis, potentially operating at several stages of cell recruitment and on several leukocyte subtypes.