Showing papers in "American Journal of Physiology-heart and Circulatory Physiology in 2017"
TL;DR: Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathoge as discussed by the authors.
Abstract: Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathoge
287 citations
TL;DR: The data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age, and an absence of age-related increases in endothelial cellsenescence in older exercising adults, which is linked with preserved vascular endothelial function.
Abstract: Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data sug...
147 citations
TL;DR: This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases.
Abstract: Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).
143 citations
University of Bristol1, Baker IDI Heart and Diabetes Institute2, Michigan Technological University3, University of Gothenburg4, University of Melbourne5, University of Alberta6, University of Mississippi Medical Center7, United States Army Research Institute of Environmental Medicine8, University of Minnesota9
TL;DR: The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.
Abstract: Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.
109 citations
TL;DR: The epidemiology, detection, risk factors, clinical significance, and pathogenesis of CMHs are reviewed, and potential treatments for the prevention are examined based on the proposed model of aging- and hypertension-dependent activation of the reactive oxygen species-matrix metalloproteinases axis.
Abstract: The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as “cerebral microbleeds”) is a significant, newly recognized problem in the aging population of the Western worl...
102 citations
TL;DR: The effects of the different training modalities in CVD are described and the molecular effects mainly in the skeletal muscle and cardiovascular system are summarized.
Abstract: For decades, we have known that exercise training exerts beneficial effects on the human body, and clear evidence is available that a higher fitness level is associated with a lower incidence of suffering premature cardiovascular death. Despite this knowledge, it took some time to also incorporate physical exercise training into the treatment plan for patients with cardiovascular disease (CVD). In recent years, in addition to continuous exercise training, further training modalities such as high-intensity interval training and pyramid training have been introduced for coronary artery disease patients. The beneficial effect for patients with CVD is clearly documented, and during the last years, we have also started to understand the molecular mechanisms occurring in the skeletal muscle (limb muscle and diaphragm) and endothelium, two systems contributing to exercise intolerance in these patients. In the present review, we describe the effects of the different training modalities in CVD and summarize the molecular effects mainly in the skeletal muscle and cardiovascular system.
94 citations
TL;DR: Novel data is provided that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins.
Abstract: This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflamma...
87 citations
TL;DR: Mass spectrometry-based profiling of circulating energy metabolites in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.
Abstract: Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid me...
85 citations
TL;DR: This review shows how the conditions of the retinal microvessels could be used to assess the condition of brain microvessel because the microvascular network of the retina and brain share, in many aspects, standard features in development, morphology, function, and pathophysiology.
Abstract: Increasing evidence suggests that the conditions of retinal microvessels are indicators to a variety of cerebrovascular, neurodegenerative, psychiatric, and developmental diseases. Thus noninvasive...
80 citations
TL;DR: In this article, the deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive PD-1 expression paralyzes the function of antitumor T cells.
Abstract: Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.
79 citations
TL;DR: The prominent differences between concentric and eccentric cardiac hypertrophy on morphological, functional, and molecular levels are delineated and are important for the precise diagnosis and treatment of these two types of cardiachypertrophy.
Abstract: Using the transverse aortic constriction mouse model and the newly developed aortic regurgitation mouse model, we delineated the prominent differences between concentric and eccentric cardiac hyper...
TL;DR: This review summarizes the available data linking ER stress to endothelial dysfunction and indicates that chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelium dysfunction.
Abstract: The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.
TL;DR: It is demonstrated that leg macrovascular function was consistently reduced in young men but not young women after prolonged sitting, and the leg microvasculature is susceptible to similar sitting-induced impairments in men and women.
Abstract: We demonstrate that leg macrovascular function was consistently reduced in young men but not young women after prolonged sitting. In contrast, both men and women exhibited similar reductions in leg...
TL;DR: The results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI2 release.
Abstract: In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) release in endothelial cells...
TL;DR: This review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it.
Abstract: Atherosclerotic peripheral artery disease primarily manifests in the medium- to large-sized conduit arteries of the lower extremities. However, the factors underlying this increased vulnerability of leg macrovasculature to disease are largely unidentified. On the basis of recent studies, we propose that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial cell dysfunction, a key predisposing factor to peripheral artery disease. In particular, this review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it.
TL;DR: It is found that the change in middle cerebral artery mean flow velocity is attenuated during hypertension compared with hypotension physiologically induced by oscillations in blood pressure in men, suggesting that the human brain is more effective at compensating for transient hypertension than hypotension.
Abstract: The novel finding of this study is that the change in middle cerebral artery mean flow velocity is attenuated during hypertension compared with hypotension physiologically induced by oscillations i...
TL;DR: This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of Autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.
Abstract: Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling Rapidly inc
TL;DR: Because of the role they play in cardiovascular disease and in age-related degeneration, oxylipins are gaining recognition as viable targets for specific dietary interventions focused on manipulatingOxylipin composition to control these biological processes.
Abstract: Oxylipins are an important group of fatty acid metabolites amenable to dietary manipulation. Because of the role they play in cardiovascular disease and in age-related degeneration, oxylipins are g...
TL;DR: It is suggested that lack of metabolic flexibility and reserve (substrate, oxidative, and phosphotransfer) represents a final common denominator ultimately compromising efficiency and contractile reserve in stressful contexts.
Abstract: The energy starvation hypothesis proposes that maladaptive metabolic remodeling antedates, initiates, and maintains adverse contractile dysfunction in heart failure (HF). Better understanding of th...
TL;DR: Comparing sympathetic innervation of the heart via the MCG vs. stellate ganglia to assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic Innervation after CSD to elucidate mechanisms of benefit are demonstrated.
Abstract: Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation in...
TL;DR: The results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics, and activating PPar-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.
Abstract: The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocard...
TL;DR: Lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults, providing evidence for a potential therapeutic use of chronic lower limb heating to improve vascular health in primary aging and various disease conditions.
Abstract: We demonstrate that lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults. These findings provide evid...
TL;DR: Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism, and is suggest to effectively improve fatigue and exercise intolerance in HF patients.
Abstract: Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enh...
TL;DR: Proof of principle is provided that acute BR supplementation can decrease central sympathetic outflow at rest and during exercise in a normotensive population and has applications for targeting central sympathetic overactivation in disease.
Abstract: Acute dietary nitrate ([Formula: see text]) supplementation reduces resting blood pressure in healthy normotensives. This response has been attributed to increased nitric oxide bioavailability and peripheral vasodilation, although nitric oxide also tonically inhibits central sympathetic outflow. We hypothesized that acute dietary [Formula: see text] supplementation using beetroot (BR) juice would reduce blood pressure and muscle sympathetic nerve activity (MSNA) at rest and during exercise. Fourteen participants (7 men and 7 women, age: 25 ± 10 yr) underwent blood pressure and MSNA measurements before and after (165-180 min) ingestion of 70ml high-[Formula: see text] (~6.4 mmol [Formula: see text]) BR or [Formula: see text]-depleted BR placebo (PL; ~0.0055 mmol [Formula: see text]) in a double-blind, randomized, crossover design. Blood pressure and MSNA were also collected during 2 min of static handgrip (30% maximal voluntary contraction). The changes in resting MSNA burst frequency (-3 ± 5 vs. 3 ± 4 bursts/min, P = 0.001) and burst incidence (-4 ± 7 vs. 4 ± 5 bursts/100 heart beats, P = 0.002) were lower after BR versus PL, whereas systolic blood pressure (-1 ± 5 vs. 2 ± 5 mmHg, P = 0.30) and diastolic blood pressure (4 ± 5 vs. 5 ± 7 mmHg, P = 0.68) as well as spontaneous arterial sympathetic baroreflex sensitivity (P = 0.95) were not different. During static handgrip, the change in MSNA burst incidence (1 ± 8 vs. 8 ± 9 bursts/100 heart beats, P = 0.04) was lower after BR versus PL, whereas MSNA burst frequency (6 ± 6 vs. 11 ± 10 bursts/min, P = 0.11) as well as systolic blood pressure (11 ± 7 vs. 12 ± 8 mmHg, P = 0.94) and diastolic blood pressure (11 ± 4 vs. 11 ± 4 mmHg, P = 0.60) were not different. Collectively, these data provide proof of principle that acute BR supplementation can decrease central sympathetic outflow at rest and during exercise. Dietary [Formula: see text] supplementation may represent a novel intervention to target exaggerated sympathetic outflow in clinical populations.NEW & NOTEWORTHY The hemodynamic benefits of dietary nitrate supplementation have been attributed to nitric oxide-mediated peripheral vasodilation. Here, we provide proof of concept that acute dietary nitrate supplementation using beetroot juice can decrease muscle sympathetic outflow at rest and during exercise in a normotensive population. These results have applications for targeting central sympathetic overactivation in disease.
TL;DR: It is shown that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung, and that this effect is also present outside the heart.
Abstract: Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially ...
TL;DR: It is suggested that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans, and is strongly correlated to shear area under the curve in the transient CO2 test.
Abstract: Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2 test, and is strongly ...
TL;DR: This systematic review aims to summarize how aerobic exercise can help to alleviate unintended cardiotoxic side effects and identify gaps in need of further research.
Abstract: Cancer and cardiovascular disease are major causes of morbidity and mortality worldwide. Older cancer patients often wrestle with underlying heart disease during cancer therapy, whereas childhood cancer survivors are living long enough to face long-term unintended cardiac consequences of cancer therapies, including anthracyclines. Although effective and widely used, particularly in the pediatric population, anthracycline-related side effects including dose-dependent association with cardiac dysfunction limit their usage. Currently, there is only one United States Food and Drug Administration-approved drug, dexrazoxane, available for the prevention and mitigation of cardiotoxicity related to anthracycline therapy. While aerobic exercise has been shown to reduce cardiovascular complications in multiple diseases, its role as a therapeutic approach to mitigate cardiovascular consequences of cancer therapy is in its infancy. This systematic review aims to summarize how aerobic exercise can help to alleviate unintended cardiotoxic side effects and identify gaps in need of further research. While published work supports the benefits of aerobic exercise, additional clinical investigations are warranted to determine the effects of different exercise modalities, timing, and duration to identify optimal aerobic training regimens for reducing cardiovascular complications, particularly late cardiac effects, in cancer survivors exposed to anthracyclines.
TL;DR: A previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1 is described, hence identifying NOV inhibition and enhanced Wnt 1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.
Abstract: The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) l
TL;DR: High-throughput screening was used to identify microRNAs that target Nox2 and improve cardiac function after infarction and this screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases.
Abstract: NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecule...
TL;DR: New evidence is provided that acetylation of cardiac mitochondrial fatty acid oxidation enzymes by GCN5L1 significantly upregulates their activity in diet-induced obese mice, and this modification is regulated in part by the activity of GCN 5L1.
Abstract: Recent research has shown that acetylation of mitochondrial fatty acid oxidation enzymes has greatly contrasting effects on their activity in different tissues Here, we provide new evidence that a