Impaired Cardiovascular Function Research Articles

Central Sleep Apnea in Heart Failure: Pathogenesis and Management

Sleep-disordered breathing (SDB) is a common comorbidity of heart failure (HF), which disrupts sleep. Indeed, patients with heart failure (HF) generally have quantitatively and qualitatively disturbed sleep. Central sleep apnea (CSA) is a unique feature of SDB in HF patients. CSA is likely a consequence, rather than a cause of HF, and results in further deterioration in cardiovascular function, consequently increasing morbidity and mortality. However, effects of treatment for CSA remain to be elucidated. This review article will highlight pathogenesis and pathophysiology of CSA and its management in patients with HF.

Role of the Renin Angiotensin System in Blood Pressure Allostasis-induced by Severe Food Restriction in Female Fischer rats

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1–8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1–8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake.

Performance Limitations in Heart Transplant Recipients.

We hypothesize that the reduced peak aerobic power (peak V˙O2) after heart transplantation is due to impaired cardiovascular and skeletal muscle function, and its improvement with short-term (≤1 yr) exercise training is primarily due to favorable skeletal muscle adaptations. Furthermore, the increased peak V˙O2 with long-term (>2 yr) training is primarily mediated by cardiac (sympathetic) reinnervation.

Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases

BackgroundRheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are common disorders associated with increased rates of cardiovascular disease (CVD), but the contribution of cytokine-induced inflammation to impaired cardiovascular function in these conditions remains poorly understood. ObjectivesWe assessed the effect of anti-TNF therapy on myocardial and vascular function, myocardial tissue characteristics and perfusion in inflammatory arthropathy and systemic rheumatic disease (IASRD) patients, using cardiovascular magnetic resonance (CMR). Methods20 RA patients, 7 AS patients, 5 PsA patients without previously known CVD scheduled to commence anti-TNF therapy and 8 RA patients on standard disease modifying antirheumatic drugs underwent CMR at 1.5 T, including cine, tagging, pulse wave velocity (PWV), T2-weighted, native and postcontrast T1 mapping, ECV quantification, rest and stress perfusion and late gadolinium enhancement (LGE) imaging. ResultsFollowing anti-TNF therapy, there was significant reversal of baseline subclinical cardiovascular dysfunction, as evidenced by improvement in peak systolic circumferential strain (p < 0.001), peak diastolic circumferential strain rate (p < 0.001), and total aortic PWV, (p < 0.001). This was accompanied by a reduction in myocardial inflammation, as assessed by T2-weighted imaging (p = 0.005), native T1 mapping (p = 0.009) and ECV quantification (p = 0.001), as well as in serum inflammatory markers like CRP (p < 0.001) and ESR (p < 0.001), and clinical measures of disease activity (DAS28-CRP, p = 0.001; BASDAI, p < 0.001). A trend towards improvement in myocardial perfusion was observed (p = 0.07). Focal myocardial fibrosis, as detected by LGE CMR was not altered by anti-TNF therapy (p = 0.92). ConclusionsAnti-TNF therapy reduces subclinical myocardial inflammation and improves cardiovascular function in RA, AS and PsA. CMR may be used to track disease progression and response to therapy. Future CMR-based studies to demonstrate effect of anti-TNF therapy modulation of vascular structure and function on hard clinical events and outcomes would be useful.

Increased susceptibility to cardiovascular disease in offspring born from dams of advanced maternal age.

Advanced maternal age increases the risk of pregnancy complications such as fetal growth restriction, hypertension and premature birth. Offspring born from compromised pregnancies are at increased risk of cardiovascular disease as adults. However, the effect of advanced maternal age on later-onset disease in offspring has not been investigated. In adulthood, male but not female offspring born to dams of advanced maternal age showed impaired recovery from cardiac ischaemia/reperfusion injury. Endothelium-dependent relaxation was also impaired in male but not female offspring born from aged dams. Oxidative stress may play a role in the developmental programming of cardiovascular disease in this model. Given the increasing trend toward delayed parenthood, these findings have significant population and health care implications and warrant further investigation. Exposure to prenatal stressors, including hypoxia, micro- and macronutrient deficiency, and maternal stress, increases the risk of cardiovascular disease in adulthood. It is unclear whether being born from a mother of advanced maternal age (≥35years old) may also constitute a prenatal stress with cardiovascular consequences in adulthood. We previously demonstrated growth restriction in fetuses from a rat model of advanced maternal age, suggesting exposure to a compromised in utero environment. Thus, we hypothesized that male and female offspring from aged dams would exhibit impaired cardiovascular function as adults. In 4-month-old offspring, we observed impaired endothelium-dependent relaxation in male (P<0.05) but not female offspring born from aged dams. The anti-oxidant polyethylene glycol superoxide dismutase improved relaxation only in arteries from male offspring of aged dams (ΔEmax : young dam -1.63±0.80vs. aged dam 11.75±4.23, P<0.05). Furthermore, endothelium-derived hyperpolarization-dependent relaxation was reduced in male but not female offspring of aged dams (P<0.05). Interestingly, there was a significant increase in nitric oxide contribution to relaxation in females born from aged dams (ΔEmax : young dam -24.8±12.1vs. aged dam -68.7±7.7, P<0.05), which was not observed in males. Recovery of cardiac function following an ischaemia-reperfusion insult in male offspring born from aged dams was reduced by ∼57% (P<0.001), an effect that was not evident in female offspring. These data indicate that offspring born from aged dams have an altered cardiovascular risk profile that is sex-specific. Given the increasing trend toward delaying pregnancy, these findings may have significant population and health care implications and warrant further investigation.

L-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex

Reduced nitric oxide (NO) bioavailability correlates with impaired cardiovascular function. NO is extremely labile and has been challenging to develop as a therapeutic agent. However, NO bioavailability could be enhanced by pharmacologically targeting endogenous NO regulatory pathways. Tetrahydrobiopterin, an essential cofactor for NO production, is synthesized by GTP cyclohydrolase-1 (GCH1), which complexes with GCH1 feedback regulatory protein (GFRP). The dietary amino acid l-phenylalanine activates this complex, elevating vascular BH4. Here, the authors demonstrate that l-phenylalanine administration restores vascular function in a rodent model of hypertension, suggesting the GCH1-GFRP complex represents a rational therapeutic target for diseases underpinned by endothelial dysfunction.

Endothelial Function And Cardiovascular Stress Markers After A Single Dive In Aging Rats (ApoE Knockout Rats)

The compressed gas breath during diving augments partial pressure of oxygen causing the oxygen concentration of the blood to increase above normal (hyperoxia). Hyperoxia in combination with gas bubbles that develop during the decompression (ascent) phase, likely causing oxidative stress, including transient endothelial dysfunction in venous and arterial vessels. The number of aging divers is rising and aging itself is associated with a gradual impairment of endothelial function. These alterations play a central role in the pathogenesis of atherosclerosis and coronary artery disease. While diving and aging are independent modulators of cardiovascular function, little is known about their combined effect. Thus, the central question is does diving expose old divers to more oxidative stress or not?MethodApoE homozygous knockouts rats with impaired cardiovascular function were used as a model for aging. 10 ApoE rats (male and female) exposed to 500 kPa heliox gas (80% helium/20% oxygen) for 1 hr in a pressure chamber to simulate diving. Endothelial function examined in‐vitro by myograph in pulmonary and mesenteric artery. The oxidative stress biomarkers measured in the plasma (collected from heart) and lung tissue via TBARS assay. 10 ApoE rats served as a control group.Results and conclusionThe results of this study demonstrated that a single dive causes endothelial dysfunction in pulmonary arteries of rats with aging cardiovascular system. This seems to be caused by reduction in NO synthesis (Fig. 1). These responses were observed just in male rats.Support or Funding InformationThis project was funded by Aarhus University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inverse association between sympathetic nervous system activity and bone mass in middle aged overweight individuals

Sympathetic nervous system activation in obesity is associated with impaired cardiovascular and metabolic function. Animal studies have shown a direct link between sympathetic nervous activation and bone health but little is known about this link in humans. This study examined whether sympathetic activation may impact bone health in overweight adults. This cross sectional study included 96 overweight or obese middle-aged adults (51 males, mean body mass index: 32.8 kg/m2, mean age: 55.3 years). Multivariate linear regression models evaluated associations between whole body and leg bone mineral density (BMD) and bone mineral content (BMC) derived from dual-energy X-ray absorptiometry and muscle sympathetic nervous system activity (MSNA) measured by microneurography. Older age, male sex and higher weight were associated with higher leg and body BMC and BMD. After adjustment for age, sex and weight, MSNA was significantly inversely associated with total BMC (p = 0.012) and with leg BMC (p < 0.01) but was not associated with either total or leg BMD (p = 0.159 and p = 0.063 respectively). When the analysis was sex specific, the relationships between MSNA and total and leg BMC were only significant in males. Our study indicates that in middle aged overweight or obese males, sympathetic activation may have a deleterious effect on bone mineral content.

Oil Exposure Impairs In Situ Cardiac Function in Response to β-Adrenergic Stimulation in Cobia (Rachycentron canadum).

Aqueous crude oil spills expose fish to varying concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs), which can have lethal and sublethal effects. The heart is particularly vulnerable in early life stages, as PAH toxicity causes developmental cardiac abnormalities and impaired cardiovascular function. However, cardiac responses of juvenile and adult fish to acute oil exposure remain poorly understood. We sought to assess cardiac function in a pelagic fish species, the cobia (Rachycentron canadum), following acute (24 h) exposure to two ecologically relevant levels of dissolved PAHs. Cardiac power output (CPO) was used to quantify cardiovascular performance using an in situ heart preparation. Cardiovascular performance was varied using multiple concentrations of the β-adrenoceptor agonist isoproterenol (ISO) and by varying afterload pressures. Oil exposure adversely affected CPO with control fish achieving maximum CPO's (4 mW g-1 Mv) greater than that of oil-exposed fish (1 mW g-1 Mv) at ISO concentrations of 1 × 10-6 M. However, the highest concentration of ISO (1 × 10-5 M) rescued cardiac function. This indicates an interactive effect between oil-exposure and β-adrenergic stimulation and suggests if animals achieve very large increases in β-adrenergic stimulation it could play a compensatory role that may mitigate some adverse effects of oil-exposure in vivo.

Chronic exposure to electronic cigarettes results in impaired cardiovascular function in mice.

Proponents for electronic cigarettes (E-cigs) claim that they are a safe alternative to tobacco-based cigarettes; however, little is known about the long-term effects of exposure to E-cig vapor on vascular function. The purpose of this study was to determine the cardiovascular consequences of chronic E-cig exposure. Female mice (C57BL/6 background strain) were randomly assigned to chronic daily exposure to E-cig vapor, standard (3R4F reference) cigarette smoke, or filtered air ( n = 15/group). Respective whole body exposures consisted of four 1-h-exposure time blocks, separated by 30-min intervals of fresh air breaks, resulting in intermittent daily exposure for a total of 4 h/day, 5 days/wk for 8 mo. Noninvasive ultrasonography was used to assess cardiac function and aortic arterial stiffness (AS), measured as pulse wave velocity, at three times points (before, during, and after chronic exposure). Upon completion of the 8-mo exposure, ex vivo wire tension myography and force transduction were used to measure changes in thoracic aortic tension in response to vasoactive-inducing compounds. AS increased 2.5- and 2.8-fold in E-cig- and 3R4F-exposed mice, respectively, compared with air-exposed control mice ( P < 0.05). The maximal aortic relaxation to methacholine was 24% and 33% lower in E-cig- and 3R4F-exposed mice, respectively, than in controls ( P < 0.05). No differences were noted in sodium nitroprusside dilation between the groups. 3R4F exposure altered cardiac function by reducing fractional shortening and ejection fraction after 8 mo ( P < 0.05). A similar, although not statistically significant, tendency was also observed with E-cig exposure ( P < 0.10). Histological and respiratory function data support emphysema-associated changes in 3R4F-exposed, but not E-cig-exposed, mice. Chronic exposure to E-cig vapor accelerates AS, significantly impairs aortic endothelial function, and may lead to impaired cardiac function. The clinical implication from this study is that chronic use of E-cigs, even at relatively low exposure levels, induces cardiovascular dysfunction. NEW & NOTEWORTHY Electronic cigarettes (E-cigs) are marketed as safe, but there has been insufficient long-term exposure to humans to justify these claims. This is the first study to report the long-term in vivo vascular consequences of 8 mo of exposure to E-cig vapor in mice (equivalent to ~25 yr of exposure in humans). We report that E-cig exposure increases arterial stiffness and impairs normal vascular reactivity responses, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease.

The Safety of Ingested Caffeine: A Comprehensive Review.

Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.

Low Plasma Protein Levels at Birth Are Associated with Poor Cardiovascular Adaptation and Serious Adverse Outcome in Infants with Gestational Age

Background: Retrospective studies suggest that early hypoproteinemia has prognostic value for adverse outcome in preemies, but the underlying pathophysiology is unknown. We hypothesized that the prognostic relevance of hypoproteinemia could be related to its association with impaired cardiovascular function and organ perfusion during transition. Objectives: To describe the plasma protein status and the measures of cardiovascular function according to the outcome in infants <32 weeks' gestation. Methods: One hundred and twenty-eight infants were prospectively included from birth to discharge. During the first 24 h of life, we assessed the cardiovascular function and systemic and organ blood flow by Doppler ultrasound, and monitored cerebral and renal regional oxygen saturation (cRSO₂, rRSO₂) using near-infrared spectroscopy. These measures were analyzed in relationship to hypoproteinemia (total plasma protein level <40 g/L at 12 h of life) and severe adverse outcome (death or survival with severe neurological injury). Results: Hypoproteinemia was associated with a higher risk of a severe adverse outcome after adjustment of confounding variables (adjusted OR = 6.8; 95% CI 1.3-34). Compared to normoproteinemic infants and after adjustment for gestational age, hypoproteinemic ones had more significantly: hypotension (7 vs. 13%, p = 0.03), abnormal capillary refilling time (20 vs. 36%, p < 0.001), abnormal renal blood flow (resistive index 0.78 ± 0.11 vs. 0.85 ± 0.09, p = 0.04), lower rRSO₂ (82.9 ± 9.2 vs. 73.6 ± 10.5%, p = 0.04), and lower systemic vascular resistance (0.155 ± 0.058 vs. 0.108 ± 0.037 mm Hg/L/kg; p = 0.04). The cRSO₂ patterns were significantly decreased in infants with severe adverse outcome and independent from protein status. Conclusion: Hypoproteinemia is associated with impaired cardiovascular function. Further studies are required to elucidate the interplay between changes in protein levels, postnatal hemodynamics and clinical outcome.

Using heat as a therapeutic tool for the aging vascular tree.

Healthy aging in humans is associated with progressive deterioration of various organ systems, the cardiovascular system being one of the most notable. Young arteries have a pronounced ability to dilate and constrict to mediate changes in blood flow in response to various stimuli (e.g. exposure to a cold or hot environment). With increasing age, complex structural and functional changes to the blood vessels occur which are further exacerbated by common comorbidities including hypertension, diabetes mellitus and hypercholesterolemia. These changes in both the endothelial and smooth muscular layers of the vasculature are mediated through impaired dilator signalling pathways (e.g. nitric oxide signaling and endothelium-derived hyperpolarizing factor) along with augmented contractile pathways (e.g. renin-angiotensin system and endothelin-1). These age-related changes along with the intimal accumulation of lipids (i.e., atherosclerosis, which can strongly impede dilator function) are thought to span the entire arterial tree. In older adults, the impairments in cardiovascular function are most evident during passive heat stress and/or exercise. Recent reports have indicated that passive exposure to heat that elicits a marked increase in body core temperature, and therefore dilation of the arterial tree, may improve macro- and microvascular dilator function in young adults. Given that older adults exhibit a greater capacity for improvement in dilator function, it is possible that chronic heat exposure, or heat therapy, could improve dilator function of the arterial tree which may have multiple health benefits.

PS 13-25 MANGIFERIN PROTECTS AGAINST MYOCARDIAL INSULTS THROUGH MODULATION OF MAPK PATHWAY

Objective: Revascularization following acute myocardial infarction leads to ischemia reperfusion injury which is associated with oxidative stress, apoptosis and inflammation leading to impaired cardiovascular function. Mangiferin is a major phytochemical and a polyphenolic antioxidant present in the bark, fruits, roots and leaves of Mangifera indica Linn (Anacardiaceae). It is known to modulate many biological targets in inflammation & oxidative stress. It also possesses anti-oxidant, anti-apoptotic; anti-atherogenic and anti-diabetic actions. Hence, we hypothesized that the antioxidative, antiinflammatory, and antiapoptotic effects of mangiferin may also be involved in the prevention of IR injury. The present study was designed to investigate whether mangiferin exerts protection against myocardial ischemia-reperfusion (IR) injury with a focus on the underlying mechanism. Design and Method: Male albino Wistar rats were divided into four groups namely sham, IR-control, Mangiferin-40+IR and Mangiferin 40 per se. Mangiferin was administered at a dose of 40 mg/kg, intraperitoneally for 15 days. On the 15th day, myocardial IR injury was induced by occluding the left anterior descending coronary artery for 45 minutes followed by reperfusion for 60 minutes. At the end of the surgical procedure, the rats were sacrificed, the hearts excised and processed. Results: IR-control rats showed significant cardiac dysfunction, raised serum cardiac injury markers, and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats revealed myocardial necrosis, edema and inflammatory cells infiltration. Pretreatment with mangiferin significantly suppressed myocardial oxidative damage, maintained membrane integrity, and attenuated the levels of proinflammatory cytokines, pro-apoptotic proteins and TGF-β. Additionally, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. Conclusions: Mangiferin protects against myocardial IR injury by alleviating oxidative stress mediated apoptosis and modulating MAPK mediated inflammation.

Links between Autonomic Dysfunction and Metabolic Syndrome

The autonomic nervous system (ANS) plays a key role in the control of a number of vital functions including cardiovascular, endocrine/neurovascular, gastrointestinal, genitourinary, pupil and thermoregulatory functions. Its abnormalities have been associated with early mortality, sudden death, silent myocardial infarction, gastrointestinal diseases. The manifestation of the ANS dysfunction in several human diseases is underestimated. Evidences exist on the important role of ANS dysfunctions in different clinically relevant conditions, including diabetes mellitus, chronic functional constipation, scleroderma, thalassemia major. Beside the classical evaluation in patients with diabetes mellitus, little is known about the effects of metabolic factors on ANS dysfunction. The metabolic syndrome (MetS) includes a cluster of frequent abnormalities (impaired fasting glycaemia, dyslipidemia, arterial hypertension and increased visceral adiposity) predisposing to the atherosclerotic changes and increased cardiovascular mortality. Early signs of autonomic dysfunction are often found in subjects with MetS even in the absence of diabetes. Epidemiological studies demonstrated that diabetics display a cardiovascular risk which is twice that of sex- and age-matched non-diabetic population. Manifestations of such a high cardiovascular risk of subjects with DM are the frequent silent myocardial infarctions (MI)s of diabetics which are often due to impaired cardiovascular autonomic function. Only recently major attention has been given to the interactions between impaired glucose tolerance (IGT) and cardiovascular autonomic dysfunctions. When increased waist circumference (one of the features of the MetS) and IGT are both present, cardiovascular autonomic dysfunction also occurs. Some adipokines (e.g. adiponectin) seem to play a role in cardiovascular risk and autonomic dysfunction. This review will therefore focus on some subtle aspects linking ANS dysfunction and MetS.

Toxicity effects of the environmental hormone 4-tert-octylphenol in zebrafish (&lt;i&gt;Danio rerio&lt;/i&gt;)

4-tert-octylphenol (4-t-OP), an environmental exogenous estrogen is produced by microbial degradation of alkylphenol polyethoxylates (APEOs). Although it is well known that 4-t-OP can cause the feminization of male, sterility and deficiency of gonad development of aquatic animals by disrupting the endocrine reproductive signaling, less is known about the effects of 4-t-OP on embryonic development. Moreover, the presence of 4-t-OP were detected in umbilical cord blood samples of newborns suggesting infants during development may expose to the risk of 4-t-OP contaminant, hence to investigate the effect of 4-t-OP on physiological function during embryonic development is necessary. In the present study, zebrafish embryos exposed to 4-t-OP were used to evaluate the toxicity of 4-t-OP. The 50% lethal dose (LD50) for wild type zebrafish embryos exposure to 4-t-OP for 3 days is approximately 1.0 mM, and a high ratio of cardiovascular defects were showed in survival embryos. To observe the cardiovascular defects more efficiently, Tg(fil-1:EGFP) zebrafish embryos was used in 4-t-OP exposure treatment. Following exposure Tg(fil-1:EGFP) zebrafish embryos to 4-t-OP at 1.0 mM for 4 days, a highly proportion of defects revealed in cardiovascular system, including pericardical edema, irregular shape or incomplete looping of ventricle and atrium, the absence of intersegmental vessel in the tail of notochord, unformed parachordal vessel and kinks in the caudal vein. The phenotype of cardiovascular defects was accompanied by reduced heart rate and impaired blood circulation. The mRNA expression levels of transcription factors, which are critical for zebrafish heart chamber formation and blood vessel development, were analyzed by RT-PCR. The results showed that the presence of 4-t-OP significantly induce expression level of ERα and ERβ2 , and caused cardiovascular defects by suppressing transcription factor Nkx2.7 , Hand2 , Tbx2a , Tbx2b , Tbx5a , FGF1a , GATA-4 , -5 and -6 in zebrafish. The present study suggests that 4-t-OP affects the cardiovascular development in zebrafish and elucidated that early life exposure to 4-t-OP potentially may take a risk of impaired cardiovascular function.

Abstract 20168: Enhanced Endothelial Nitric Oxide Production and Cardiac Dysfunction in an Inducible Endothelial-Specific miR-130a Mouse Model

Introduction: MicroRNA-130a (miR130a) has been shown to be important in cardiovascular gene regulation in both normal and diseased states. We recently reported on the regulation of connexin43 by miR130a. Methods: We created an inducible mouse model to express miR-130a in endothelial cells under the control of the VE-cadherein promoter (VE-cad-miR130a). Overexpression of miR-130a was initiated in adult mice at weaning, approximately 4 weeks post-birth. Results: Survival analysis revealed &gt;50% mortality by 9 weeks of age with overexpression of miR-130a. By 9 weeks of age, LV function was reduced (26.4% ± 4 vs 33.6% ± 6 in controls, p&lt;0.001, n=10). Prior to the onset of LV dysfunction; we found numerous abnormalities in cardiac function. First, we noted significant bradycardia on ambulatory telemetric recordings (389bpm ± 90 vs 534bpm ± 72 in controls, p&lt;0.0001, n=3). Moreover, the cardiac response to β-AR stimulation was blunted in VE-Cad-miR130a mice relative to control when challenged with isoproterenol. Interestingly, sinus node recovery time was significantly prolonged, supportive of sinus node dysfunction. While predominately in sinus rhythm, we found episodes of spontaneous atrial tachyarrhythmias, which were confirmed on invasive electrophysiologic testing. To investigate further, we performed patch clamp measurements of action potential duration (APD) in atrial cariomyocytes. APD was significantly prolonged in VE-Cad-miR130a myocytes (APD90 325ms vs 60ms, p&lt;0.00001, n=3). Next, we performed invasive blood measure measurements and found a significant decrease in mean arterial blood pressure (76.9mmHg ± 3 vs 94.3mmHg ± 5 in controls, p&lt;0.01, n=4). Based on previous reports of increased nitric oxide in the setting of loss of endothelial connexin43, we found significant elevation of NO concentration in VE-Cad-miR130a. Inhibition of NO synthase via IP administration of L-NAME increased MAP in VE-Cad-miR130a to a maximum steady-state mimicking that of control mice. Conclusions: Overexpression of miR-130a in endothelial cells promotes impaired cardiovascular function and abnormal atrial conduction. These results suggest a newly identified role for endothelial miR-130a in the development of hypotension and cardiac dysrhythmias.

Arjunolic acid ameliorates reactive oxygen species via inhibition of p47phox-serine phosphorylation and mitochondrial dysfunction

Impaired cardiovascular function during acute myocardial infarction (MI) is partly associated with recruitment of activated polymorphonuclear neutrophils. The protective role of arjunolic acid (AA; 2,3,23-trihydroxy olean-12-en-28-oic acid) is studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation. Neutrophils were isolated from normal and acute MI mice to find out the efficacy of AA in reducing oxidative stress. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) resulted in an oxidative burst of superoxide anion (O2−) and enhanced release of lysosomal enzymes. The treatment of neutrophils with PMA induced phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase. Furthermore, we observed activated ERK induced phosphorylation of Ser345 in MI neutrophils. Treatment with AA significantly inhibited the phosphorylation of P47phox and ERK in the stimulated controls and MI neutrophils. Oxidative phosphorylation activities in MI cells were lower than in control, while the glycolysis rates were elevated in MI cells compared to the control. In addition, we observed AA decreased intracellular oxidative stress and reduced the levels of O2− in neutrophils. This study therefore identifies targets for AA in activated neutrophils mediated by the MAPK pathway on p47phox involved in ROS generation.

CO2 pulse and acid-base status during increasing work rate exercise in health and disease

The CO2 pulse (V˙CO2/heart rate), analogous to the O2 pulse (V˙O2/heart rate), was calculated during cardiopulmonary exercise testing and evaluated in normal and diseased states. Our aim was to define its application in its release in excess of that from V˙CO2/heart rate in the presence of impaired cardiovascular and lung function. In the current study, forty-five patients were divided into six physiological states: normal, exercise-induced myocardial ischemia, chronic heart failure, pulmonary vasculopathy, chronic obstructive pulmonary disease, and interstitial lung disease. We subtracted the O2 pulse from the CO2 pulse to determine the exhaled CO2 that could be attributed to CO2 pulse of buffering of lactic acid. The difference between the CO2 pulse and O2 pulse (V˙CO2/heart rate–V˙O2/heart rate) includes CO2 generated from HCO3− buffering of lactic acid. The accumulated CO2 per body mass was found to be significantly correlated with the corresponding [HCO3−] decrease (R2=0.72; P<0.0001). In summary, the increase in CO2 pulse over the O2 pulse accounted for the anaerobically-generated excess-CO2 in each of the physiological states and correlated with the decreases in the arterial Bicarbonate concentration.

Hypertension Editors’ Picks

<i>Hypertension</i> Editors’ Picks