End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation

2009 ◽  
Vol 116 (3) ◽  
pp. 175-190 ◽  
Author(s):  
Christopher J. Lockhart ◽  
Paul K. Hamilton ◽  
Cathy E. Quinn ◽  
Gary E. McVeigh
Keyword(s):  
Cardiovascular Disease ◽  
Organ Dysfunction ◽  
Inflammatory Responses ◽  
Structure And Function ◽  
Therapeutic Interventions ◽  
Pivotal Role ◽  
Vascular Effects ◽  
Microvascular Damage ◽  
Arterial Blood ◽  
And Function

Risk factors for cardiovascular disease mediate their effects by altering the structure and function of wall and endothelial components of arterial blood vessels. A pathological change in the microcirculation plays a pivotal role in promoting end-organ dysfunction that not only predisposes to further organ damage, but also increases the risk for future macrovascular events. The microcirculation is recognized as the site where the earliest manifestations of cardiovascular disease, especially inflammatory responses, occur that may play a pivotal role in driving the atherosclerotic process in conduit vessels. Furthermore, the vast surface area of the endothelium compared with conduit vessels means that the vascular effects of endothelial dysfunction or activation will be most apparent in this section of the vasculature. Current techniques providing indices of vascular health focus on large arteries without providing insight into the structure and function of small vessels. Techniques capable of detecting microvascular damage and monitoring the response to therapeutic interventions, especially in vulnerable target organs of interest, may improve risk stratification and represent a valuable surrogate for future cardiovascular outcome.

scholarly journals Deubiquitylating enzymes in neuronal health and disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fatima Amer-Sarsour ◽  
Alina Kordonsky ◽  
Yevgeny Berdichevsky ◽  
Gali Prag ◽  
Avraham Ashkenazi
Keyword(s):  
Human Brain ◽  
Neurodegenerative Disorders ◽  
Structure And Function ◽  
Pivotal Role ◽  
Protein Homeostasis ◽  
Neuronal Function ◽  
Health And Disease ◽  
And Function

AbstractUbiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease.

Abstract P138: Long-term Effects Of Severe Caloric Restriction To The Heart Function

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Aline M De Souza ◽  
Jonathas Almeida ◽  
Nataliia Shults ◽  
Hong Ji ◽  
Kathryn Sandberg
Keyword(s):  
Cardiovascular Disease ◽  
Caloric Restriction ◽  
Heart Function ◽  
Left Ventricular ◽  
Structure And Function ◽  
Long Term Effects ◽  
Isolated Hearts ◽  
Ad Libitum ◽  
And Function

Severe caloric restriction (sCR) increases the risk for acute cardiovascular disease. Less understood are the long-term effects on cardiovascular disease risk after the sCR period has ended. We investigated the effects of sCR on heart structure and function months after refeeding (sCR-Refed). Female Fischer rats (3-months-old) were maintained on (CT) ad libitum or a 60% caloric restricted diet for 2 weeks. Thereafter, all rats received ad libitum chow for 3 months and they were analyzed by precision ultrasound to assess their heart function. After imaging, the animals were sacrificed and the hearts were subjected to ischemia-reperfusion (I/R) using a Langendorff preparation. After 2 weeks of sCR, rats lost 15% of their initial body weight (BW) [% (100*(Final-Initial/Initial)): CT, 1.5±0.8 vs sCR, -15.4±1.1; p<0.001;n=8]. After 3 months of refeeding, there was no detectable difference in BW between CT and sFR-Refed groups. Isolated hearts from the sCR-Refed rats exhibited worse myocardial pathology after I/R compared to CT rats. The parallel orientation of myofibers and striations normally present in cardiomyocytes was lost in sCR-Refed rats. Further analysis revealed uneven blood-filling of the microcirculatory vessels and prominent interstitial edema of the myocardium. Hearts from sCR-Refed rats had more atrophied cardiomyocytes than CT [Atrophied/Total (%): CT, 0.2±0.1 vs sCR-Refed, 50.6±1.1; p<0.001; n=5]. The number of arrhythmic events during a 30 min ischemic interval in isolated hearts doubled after 2 weeks on the sCR diet ( data not shown ) and remained doubled 3 months later [Arrhythmias (% of time): CT, 34±8 vs sCR-Refed, 68±9; p=0.02; n=8]. Ultrasound imaging showed no difference in stroke volume, coronary perfusion pressure and left ventricular mass. However, the thickness of the left ventricular posterior wall was significantly reduced in sCR-Refed rats [(mm): CT, 2.55 ±0.03 vs sCR-Refed, 2.10±0.04; p=0.002; n=4]. These findings indicate heart structure and function remained damaged months after the sCR period ended and BW was restored. These studies have adverse cardiovascular risk implications for who are subjected either voluntarily (crash diets) or involuntarily (very low food security) to periods of inadequate caloric intake.

scholarly journals P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Junteng Zhou ◽  
Zhichao Zhou ◽  
Xiaojing Liu ◽  
Hai-Yan Yin ◽  
Yong Tang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
P2x7 Receptor ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Experimental Studies ◽  
Therapeutic Interventions ◽  
Receptor Protein ◽  
Inflammasome Activation

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

Is the renal production of erythropoietin controlled by the brain stem?

2005 ◽  
Vol 289 (1) ◽  
pp. E82-E86 ◽  
Author(s):  
Ursula von Wussow ◽  
Janina Klaus ◽  
Horst Pagel
Keyword(s):  
Blood Pressure ◽  
Brain Stem ◽  
Structure And Function ◽  
Humoral Factors ◽  
Arterial Blood ◽  
Arterial Ph ◽  
Sensitive Sensor ◽  
Releasing Factors ◽  
And Function ◽  
The Brain

Although the structure and function of erythropoietin (Epo) are well documented, the mechanisms of the regulation of the renal synthesis of Epo are still poorly understood. Especially, the description of the localization and function of the O2-sensitive sensor regulating the renal synthesis of Epo is insufficient. A body of evidence suggests that extrarenal O2-sensitive sensors, localized particularly in the brain stem, play an important role in this connection. To support this concept, high cerebral pressure with consecutive hypoxia of the brain stem was generated by insufflation of synthetic cerebrospinal fluid into the catheterized cisterna magna of rats. When the cerebral pressure of the rats was above the level of their mean arterial blood pressure or the high cerebral pressure persisted for a longer period (≥10 min), the Epo plasma concentration increased significantly. Bilateral nephrectomy or hypophysectomy before initiation of high intracranial pressure abolished this effect. Systemic parameters (heart rate, blood pressure, PaO2, PaCO2, arterial pH, renal blood flow, glucose concentration in blood) were not affected. Other stressors, like restricting the mobility of the rats, had no effect on Epo production. Hence, the effect of high cerebral pressure on renal synthesis of Epo seems to be specific. Increasing cerebral hydrostatic pressure leads to increased renal synthesis of Epo. Obviously, during hypoxia, cerebral O2-sensitive sensors release humoral factors, triggering the renal synthesis of Epo. The structure and function of these “Epo-releasing-factors” will have to be characterized in future experiments.

Repair and recovery mechanisms following critical illness

2016 ◽  
Author(s):  
Geoffrey Bellingan ◽  
Brijesh V. Patel
Keyword(s):  
Critical Illness ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Structure And Function ◽  
Tissue Structure ◽  
Inflammatory Activation ◽  
Recovery Mechanisms ◽  
And Function

Inflammation is the beneficial host response to foreign challenge or tissue injury that ultimately leads to the restoration of tissue structure and function. Critical illness is associated with an overwhelming and prolonged inflammatory activation. Resolution of the inflammatory response is an active process that requires removal of the inciting stimuli, cessation of the pro-inflammatory response, a timely coordinated removal of tissue leukocyte infiltration, a conversion from ‘toxic’ to reparative tissue environment, and restoration of normal tissue structure and function. Mortality may result from deficits in these resolution mechanisms. Improved delivery of critical care through prevention of harm and removal of stimuli has already delivered significant mortality benefits. Most critically-ill patients present with uncontrolled inflammation, hence anti-inflammatory strategies ameliorating this response are likely to be too late and thus futile. Rather, strategies augmenting endogenous pathways involved in the control and appropriate curtailment of such inflammatory responses may promote resolution, repair, and catabasis. Recent evidence showing that inflammation does not simply ‘fizzle out’, but its resolution involves an active and coordinated series of events. Dysfunction of these resolution checkpoints alters the normal inflammatory pathway, and is implicated in the induction and maintenance of states such as ARDS and sepsis. Improved understanding of resolution biology should provide translational pathways to not only improve survival, but also to prevent long-term morbidity resulting from tissue damage.

scholarly journals Impact of Health Status and Lifestyle Modifications on Vascular Structure and Function in Children and Adolescents

2015 ◽  
Vol 11 (4) ◽  
pp. 330-343
Author(s):  
Donald R. Dengel ◽  
Justin R. Ryder
Keyword(s):  
Cardiovascular Disease ◽  
Children And Adolescents ◽  
Vascular System ◽  
Disease Process ◽  
Structure And Function ◽  
Vascular Structure ◽  
Lifestyle Modifications ◽  
Genetic Abnormalities ◽  
And Function ◽  
Reliable Methods

Until recently cardiovascular disease is often thought of as a disease that manifests itself during middle age. Researchers and clinicians have begun to realize that the initial signs of cardiovascular disease begin early on in childhood with changes present in both vascular structure and function. This increased recognition has resulted in considerable effort to develop accurate and reliable methods to measure as well as track changes in vascular structure and function applicable to study this process in children and adolescents. Certain genetic abnormalities and chronic diseases, which present or emerge in childhood often result in meaningful changes to vascular structure and function, which aid in our understanding of the vascular disease process. In this review, we will discuss different methods of assessing vascular structure and function, the diseases in childhood associated with decrements and maladaptive changes in the vascular system, and whether modification of lifestyle (ie, weight loss, dietary and/or exercise changes) can affect vascular structure and function in children.

scholarly journals Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

2016 ◽  
Vol 96 (3) ◽  
pp. 1127-1168 ◽  
Author(s):  
Samuel Golpanian ◽  
Ariel Wolf ◽  
Konstantinos E. Hatzistergos ◽  
Joshua M. Hare
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Coronary Vessels ◽  
Heart Tissue ◽  
Structure And Function ◽  
Nonischemic Cardiomyopathy ◽  
Cell Based Therapy ◽  
And Function

Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.

The history of the capillary wall: doctors, discoveries, and debates

2007 ◽  
Vol 293 (5) ◽  
pp. H2667-H2679 ◽  
Author(s):  
Charlotte Hwa ◽  
William C. Aird
Keyword(s):  
Basic Structure ◽  
Structure And Function ◽  
The Body ◽  
Capillary Wall ◽  
Central Importance ◽  
Definitive Evidence ◽  
Arterial Blood ◽  
History Of ◽  
And Function

In 1628, William Harvey provided definitive evidence that blood circulates. The notion that blood travels around the body in a circle raised the important question of how nutrients pass between blood and underlying tissue. Perhaps, Harvey posited, arterial blood pours into the flesh as into a sponge, only then to find its way into the veins. Far from solving this problem, Marcello Malpighi's discovery of the capillaries in 1661 only added to the dilemma: surely, some argued, these entities are little more than channels drilled into tissues around them. As we discuss in this review, it would take over 200 years to arrive at a consensus on the basic structure and function of the capillary wall. A consideration of the history of this period provides interesting insights into not only the central importance of the capillary as a focus of investigation, but also the enormous challenges associated with studying these elusive structures.

scholarly journals Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

2019 ◽  
Author(s):  
Genevieve C. K. Wilson ◽  
Ada Buvoli ◽  
Massimo Buvoli ◽  
Kathleen C. Woulfe ◽  
Lori A. Walker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Structure And Function ◽  
Muscle Disease ◽  
Therapeutic Interventions ◽  
Small Subset ◽  
Histological Structure ◽  
Distal Myopathy ◽  
Myosin Binding ◽  
And Function ◽  
Myosin Rod

AbstractIntroductionMore than 400 mutations in β-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.MethodsBecause mice have very few slow skeletal muscles compared to humans, we generated mice expressing the β-myosin R1500P mutation or WT β-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation.ResultsThe mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules. Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate.ConclusionsWhile each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.

Sign in / Sign up

Export Citation Format

Share Document