Peripheral Vasodilation Research Articles

FEATURES OF CHANGES IN THE LEVELS OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION AFTER RENAL DENERVATION

Objective: The family of matrix metalloproteinases (MMPs) involved in fibrogenesis, but the effect of renal denervation (RDN) on their levels is currently insufficiently studied and highly controversial. The aim of study was to evaluate the change in MMPs and their inhibitors during 2 years after RDN in patients with resistant hypertension (RHTN) and type 2 diabetes mellitus (DM). Design and method: Forty three patients with RHTN and type 2 DM were included in single-arm prospective interventional studies (protocol numbers NCT01499810 and NCT02667912 on ClinicalTrials.gov) (mean age 60.6 ± 8.8 years, mean office (systolic/diastolic) blood pressure (BP) 169.7/89.1 ± 19.2/15.2mmHg, HbA1c 6.7 ± 1.4%, 17(40%) men). All patients were undergone to ambulatory 24-hour BP and assessment of lab testes (plasma concentrations of MMP-9, MMP-2, tissue inhibitor of MMP type 1 (TIMP1), TIMP-1/MMP-2 and TIMP-1/MMP-9 ratios) at baseline and at 6–12–24 months follow-up. The patients were advised not to change their medication regimen during the study. Results: At baseline 70%/16%/17% of patients had an elevated level of MMP-9/MMP-2/TIMP-1, respectively. At 6 months after RDN there was a significant decrease in mean 24-hour systolic/diastolic BP (SBP/DBP) (-8.8 [95%CI -1.3;-18.4]/-8.6 [95%CI -2.5;-4.7] mmHg, P < 0.05). The number of responders (patients with decrease in 24-hour SBP 10 mmHg and more) was 26 (61%). There were no significant changes in the mean levels of MMPs, TIMT1 and their ratios at 6-12-24 months follow up. At the same time, at 2 years after RDN there was a significant decrease in level of MMP-9 in responders compared with non-responders (-319.6[-2.3;-636.8] ng/mL, p = 0.04 vs 66.6 [221.4;-354.5] ng/mL, p = 0.63). Conclusions: Our data indicate the decrease in the MMP-9 level at 2 years after RDN only in the responders, that may be due to a decrease in the hemodynamic load and peripheral vasodilation that no longer requires the involving of proteolytic systems for an improvement in tissue blood flow.

Current pathophysiological concepts of acute decompensation in patients with liver cirrhosis and prognostic scores in different stages of disease

Acute decompensation and acute-on chronic liver failure (ACLF) are associated with a significant reduced prognosis. Previously, the pathophysiological concept of acute decompensation was mainly based on the peripheral vasodilatation hypothesis. However, during the last years, systemic inflammation was recognized as a major driver for decompensation of liver cirrhosis and ACLF. Further, it has been shown that systemic inflammation is associated with the clinical course and the prognosis of the patients. Inflammation also affects the function of extrahepatic organs and therefore leads to the development of an inflammatory cirrhotic multi-organ syndrome. The importance of systemic inflammation in the context of decompensated liver cirrhosis is also transferred to new clinical scores such as the CLIF-C AD and CLIF-C ACLF score. In this article, we provide an overview of the new systemic inflammation hypothesis of decompensated cirrhosis and also discuss current clinical scores for prognostication in different stages of liver cirrhosis.

P185 META–ANALYSIS OF PLACEBO–CONTROLLED TRIALS OF LEVOSIMENDAN IN ACUTE MYOCARDIAL INFARCTION

Abstract Introduction Despite the potential beneficial effects in the acute phase of myocardial infarction, the use of Levosimendan in recent guidelines is currently limited to patients with heart failure and a severe reduction in cardiac output not responding to standard therapy. In spite of everything, the haemodynamic effects of the drug that reduces afterload, the beneficial pleiotropic effects on myocardial stunning and the improvement of microcirculatory indices make Levosimendan still an interesting therapeutic prospect in AMI. Purpose of the Study The study aimed to analyse the available data of the use of Levosimendan in the acute setting of myocardial infarction Materials and Methods This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) and was conducted and presented according to best practice recommendations, including the Preferred Reporting Items for Systematic Reviews and Meta–Analyses (PRISMA) reporting guidelines. Seven selected studies were included in the meta–analysis. Meta–Analysis Levosimendan treatment was associated with a reduction in one year mortality and adverse event rates, without inconsistency. A trend of the increase of cardiac index and reduction of wedge pressure was evident, with an inconsistent effect on blood pressure and heart rate. No evidence of small study effects was found upon the inspection of funnel plots or regression tests. Finally, possibly given the limited number of included studies, metaregression analysis did not identify any major effect modifier. Discussion A clearly significant mortality reduction in the acute phase and long–term mortality induced by Levosimendan in AMI is evident. In the acute ischemic field, the haemodynamic properties of Levosimendan may explain part of the benefits. Levosimendan, over an inotropic effect, has a positive effect on ventriculo–arterial coupling, peripheral vasodilation consequently increasing tissue perfusion, anti–stunning effects and anti–inflammatory effects. Conclusions Our data support the idea that Levosimendan may already have a role in the treatment of acute ischemic heart disease. Further studies, specifically designed to investigate the early role in the treatment of ischemic heart failure are needed.

Increased Muscle Sympathetic Nerve Activity with Acute Hyperinsulinemia: Role of Insulin‐stimulated Peripheral Vasodilation and the Response of the Arterial Baroreflex

ObjectiveHyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP).MethodsIn 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m2) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s).ResultsInsulin infusion increased MSNA (p=0.05) and decreased TPR (p<0.05), with no effects on arterial baroreflex sensitivity or BP (p>0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p>0.05). Similar to insulin, SNP increased MSNA (p<0.01) and decreased TPR (p<0.05), with no effect on baroreflex sensitivity (p>0.05).ConclusionsPresent findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

Acute Effect of Intermittent Hypoxia on Peripheral Vascular Function in Young Healthy Adults

Continuous exposure to hypoxia elicits a chemoreceptor‐mediated increase in sympathetic nerve activity and a simultaneous peripheral vasodilation due to an increase in nitric oxide production. The aim of the present study was to determine whether short, repeated bouts of hypoxia induce brachial artery vasodilation and acutely improve endothelial function. Ten young healthy adults (4 women, age: 24±3 years, height: 176±9 cm, body weight: 80±13 kg) visited the laboratory on two separate occasions. Endothelium‐dependent vasodilation was assessed by brachial artery flow‐mediated dilation using a semiautomated diagnostic ultrasound system before and after exposure to either intermittent hypoxia (IH) or intermittent normoxia (IN). Intermittent hypoxia consisted of eight 4‐min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with breathing room air to resaturation, and intermittent normoxia consisted of eight 4‐min normoxic cycles separated by one minute of breathing room air. Air was made hypoxic by titrating nitrogen into a breathing circuit. Brachial artery diameter was assessed via ultrasound throughout the protocols. Hemodynamics, arterial oxygen saturation, and pulmonary gas exchange were also continuously assessed during the protocols. By design, intermittent hypoxia resulted in an arterial oxygen saturation of 81±2%, corresponding to oxygen levels of 11.9±2.2%. Exposure to intermittent hypoxia, but not intermittent normoxia, elicited a brachial artery vasodilation (IH: 0.38±0.06 to 0.40±0.06 vs. IN: 0.38±0.06 to 0.38±0.06 cm, p<0.01). However, neither intermittent hypoxia nor intermittent normoxia acutely affected brachial artery flow‐mediated dilation (IH: 5.8±1.9 to 5.3±1.6% vs. IN: 6.1±2.4 to 6.5±1.7%, p=0.96). Intermittent hypoxia increased cardiac output (5.2±0.9 to 5.9±1.4 L·min‐1, p=0.03) mainly due to an increase in heart rate (57±9 to 68±11 bpm, p<0.01). In conclusion, exposure to intermittent hypoxia triggered a brachial artery vasodilation but did not affect endothelium‐dependent vasodilation in young healthy adults. Multiple sessions of intermittent hypoxia may be necessary to improve nitric oxide synthesis and endothelial function.

Effect of Hyperinsulinemia on Cerebral Autoregulation and Myogenic Control of Cerebral Blood Flow in Healthy Young Adults

ObjectiveHyperinsulinemia has marked vasodilatory effects within the skeletal muscle vasculature in healthy young adults; however, the magnitude of insulin‐stimulated cerebrovascular vasodilation is less clear. Differences between circulations may be due to a greater importance of the cerebral circulation to maintain a constant level of blood flow (i.e., cerebral autoregulation) during hyperinsulinemia. We hypothesized cerebral autoregulation would increase during hyperinsulinemia. Autoregulatory mechanisms, such as myogenic control, play important roles in mediating cerebral vasomotor responses. Thus, we further sought to examine the contribution of the myogenic mechanism to the control of cerebral blood flow during hyperinsulinemia.MethodsMiddle cerebral artery blood velocity (MCAv) and femoral artery blood velocity (FAV) were measured with Doppler ultrasound and femoral artery blood flow (FBF) was calculated in 17 healthy adults (11M/6F, 28±2 yrs, 24±1 kg/m2) at baseline and following a hyperinsulinemic (40 mU/m2body surface area/min), euglycemic infusion. Finger plethysmography was used to assess mean blood pressure (MBP). Normalized transfer function gain between changes in MBP and MCAv were estimated in the 0.02‐0.07 Hz (very low frequency, VLF) and 0.07–0.20 Hz (low frequency, LF) ranges using the Welch method. Interactions between MBP and MCAv or FAV were determined using cross‐correlation analyses.ResultsIntravenous insulin infusion increased plasma insulin concentrations (6±1 to 50±3 μIU/mL, p<0.01) with blood glucose maintained at baseline levels (p=0.33). There was a significant increase in FBF (121±15 to 151±19 mL/min, p=0.03) during hyperinsulinemia, with no change in MCAv (61±4 to 59±4 cm/s, p=0.28) or MBP (86±2 to 89±2 mmHg, p=0.10). There was no effect of hyperinsulinemia on normalized transfer function gain in the VLF (p=0.25) or LF ranges (p=0.46). Hyperinsulinemia had no effect on the association between MBP and MCAv (p=0.15) or FAV (p=0.82).ConclusionsHyperinsulinemia in healthy young adults elicits peripheral vasodilation, but no change in MCAv. Contrary to our hypothesis, the sensitivity of the cerebrovascular circulation to changes in MBP (i.e., cerebral autoregulation) is not altered during systemic hyperinsulinemia in healthy adults. Furthermore, the contribution of the myogenic mechanism to the control of blood flow in the peripheral and cerebral circulations is unaffected by hyperinsulinemia. Whether these results translate to disease states (e.g., diabetes) and the implications for cerebrovascular health warrant further exploration.

Hypoxic Vasodilation is Augmented During the High versus Low Estrogen Phase of the Menstrual and Oral Hormonal Contraceptive Pill Cycle

BackgroundHypoxia elicits peripheral vasodilation to preserve oxygen delivery to metabolically active tissue. Hypoxic vasodilation, predominantly mediated by β‐adrenergic and nitric oxide mechanisms, is greater in adult female participants compared to adult male participants. Greater circulating estrogen in adult females has been purported to contribute to observed sex differences in hypoxic vasodilation. Nearly 80% of adult females in the United States will take oral hormonal contraceptive pills (OCPs) in their lifetime. Adult females taking OCPs exhibit greater β‐adrenergic receptor mediated vasodilation and nitric oxide production relative adult females with natural menstrual cycles (NC). Strategically utilizing the fluctuations of circulating estrogen that occur within a NC and OCP cycle, we aimed to examine the contribution of endogenous and exogenous estrogen on hypoxic vasodilation in female participants. We hypothesized female participants taking OCPs would exhibit greater hypoxic vasodilation relative to female participants with a NC. We further hypothesized hypoxic vasodilation would be greatest during the high estrogen (HE) phase of the menstrual or pill cycle compared to the low estrogen (LE) phase.MethodsTen female participants with a NC (25±1 yrs, 23±1 kg/m2) and ten female participants taking monophasic OCPs (24±1 yrs, 21±1 kg/m2) completed two study visits (IRB #2011312, NCT03606434). Participants were studied once during the LE phase of the menstrual or pill cycle (Cycle day: NC 3±1; OCP 5±1) and once during the HE phase of the menstrual or pill cycle (Cycle day: NC 15±1; OCP: 17±1). Forearm blood flow (venous occlusion plethysmography) and blood pressure (BP, finger plethysmography) were measured during normoxia and hypoxia (80% SpO2). Blood flow was normalized for BP and expressed as forearm vascular conductance (FVC).ResultsHypoxia elicited an increase in FVC (% change from baseline) that was greater during the HE phase (NC: 21±10%, OCP: 41±6%) of the menstrual/pill cycle compared to the LE phase (NC: 5±8%, OCP: 10±8%) in both NC and OCP participants (Main effect of phase, p<0.01; Main effect of group, p=0.16; Interaction of phase and group, p=0.30).ConclusionHypoxic vasodilation is augmented in the HE phase of the menstrual and pill cycle in healthy young female participants, independent of whether the hormone is endogenous (NC) or exogenous (OCP). These data further our understanding of the role of estrogen in hypoxic vasodilation. These findings may have clinical implications for the vascular response to hypoxia in conditions of low estrogen (i.e., postmenopause) and/or estrogen excess, and warrant further investigation.

Scapular renal cell carcinoma metastasis as a cause of high-output heart failure: a case report

BackgroundHigh-output heart failure is a rare condition that occurs when the heart is unable to respond to a sustained increase in blood demand. On echocardiography, a cardiac index of > 4 L/min/m2 (or 6 L/min) is a clear indicator of this disorder. The causes of high-output heart failure vary, but they all involve peripheral vasodilation or arteriovenous shunting. Renal cell carcinoma is well known for producing high levels of angiogenic growth factors that induce arteriovenous shunts. The decrease in peripheral arterial resistance and the increase in venous return result in a permanent high cardiac output, followed by congestive heart failure. Single bone metastases of renal clear cell carcinoma tumours causing high cardiac output and heart failure symptoms have been reported less than ten times in the medical literature.Case presentationBefore a right-shoulder painful lump with a murmur when auscultated, magnetic resonance imaging revealed a large scapular mass, which was biopsied and found to be a bone metastasis of renal cell carcinoma. Two months later, the patient developed heart failure for the first time. There was no evidence of cardiac disease on echocardiography. The cardiac output was 9.8 L/min and the cardiac index was 5.1 L/min/m2. Doppler ultrasound revealed numerous arteriovenous shunts in the large scapular metastasis and a right axillary artery flow of 24% of cardiac output. Sustained lower cardiac output was obtained following lesion-focused radiotherapy and systemic antiangiogenic treatment with axitinib and pembrolizumab.ConclusionsHerein, we present a unique case of high-output heart failure in a 70-year-old man diagnosed by echocardiography and upper-limb Doppler ultrasound in the context of metastatic renal cell carcinoma without pre-existing cardiac disease. We stress the potentially life-threatening hemodynamic consequences of hypervascularity associated with arteriovenous shunts within a single metastatic renal cell carcinoma implant, the importance of auscultating any progressing bone mass, and the utility of non-invasive Doppler ultrasound assessment in this setting.

Recovery of organ-specific tissue oxygen delivery at restrictive transfusion thresholds after fluid treatment in ovine haemorrhagic shock

BackgroundFluid resuscitation is the standard treatment to restore circulating blood volume and pressure after massive haemorrhage and shock. Packed red blood cells (PRBC) are transfused to restore haemoglobin levels. Restoration of microcirculatory flow and tissue oxygen delivery is critical for organ and patient survival, but these parameters are infrequently measured. Patient Blood Management is a multidisciplinary approach to manage and conserve a patient’s own blood, directing treatment options based on broad clinical assessment beyond haemoglobin alone, for which tissue perfusion and oxygenation could be useful. Our aim was to assess utility of non-invasive tissue-specific measures to compare PRBC transfusion with novel crystalloid treatments for haemorrhagic shock.MethodsA model of severe haemorrhagic shock was developed in an intensive care setting, with controlled haemorrhage in sheep according to pressure (mean arterial pressure 30–40 mmHg) and oxygen debt (lactate > 4 mM) targets. We compared PRBC transfusion to fluid resuscitation with either PlasmaLyte or a novel crystalloid. Efficacy was assessed according to recovery of haemodynamic parameters and non-invasive measures of sublingual microcirculatory flow, regional tissue oxygen saturation, repayment of oxygen debt (arterial lactate), and a panel of inflammatory and organ function markers. Invasive measurements of tissue perfusion, oxygen tension and lactate levels were performed in brain, kidney, liver, and skeletal muscle. Outcomes were assessed during 4 h treatment and post-mortem, and analysed by one- and two-way ANOVA.ResultsEach treatment restored haemodynamic and tissue oxygen delivery parameters equivalently (p > 0.05), despite haemodilution after crystalloid infusion to haemoglobin concentrations below 70 g/L (p < 0.001). Recovery of vital organ-specific perfusion and oxygen tension commenced shortly before non-invasive measures improved. Lactate declined in all tissues and correlated with arterial lactate levels (p < 0.0001). The novel crystalloid supported rapid peripheral vasodilation (p = 0.014) and tended to achieve tissue oxygen delivery targets earlier. PRBC supported earlier renal oxygen delivery (p = 0.012) but delayed peripheral perfusion (p = 0.034).ConclusionsCrystalloids supported vital organ oxygen delivery after massive haemorrhage, despite haemodilution to < 70 g/L, confirming that restrictive transfusion thresholds are appropriate to support oxygen delivery. Non-invasive tissue perfusion and oximetry technologies merit further clinical appraisal to guide treatment for massive haemorrhage in the context of Patient Blood Management.

Management of Pulmonary Hypertension Secondary to Valvular Heart Disease with Angiotensin-Receptor Neprilysin Inhibitor

<h3>Introduction</h3> Pulmonary hypertension secondary to left-sided valvular disease (VHD-PH) is associated with high morbidity and mortality. Angiotensin-receptor neprilysin inhibitor (ARNI) is a novel pharmacotherapy, which reduces afterload with natriuresis and peripheral vasodilation. Whether ARNI can also reduce pulmonary vasculature resistance is unknown. We present two cases of VHD-PH that improved after treatment with ARNI. <h3>Case Report</h3> Case 1: Ms. M is a 63-year-old woman with past medical history of rheumatic mitral valve (MV) stenosis (mean gradient = 12 mm Hg at a heart rate = 69 beats/minute) who presented with New York Heart Association (NYHA) Class IIIB symptoms. The initial workup showed normal left ventricular function (LV) but severe combined pre- and post-capillary PH (Cpc-PH). She was deemed to be a high-risk surgical candidate given the severity of PH. Subsequently, she was treated with ARNI for three months, and repeat right heart catheterization showed significant improvement in Cpc-PH (see Table). Case 2: Mr. S is a 59-year-old man with past medical history of MV endocarditis s/p remote bovine MV replacement in 1984 complicated by paravalvular leak and redo replacements who presented with worsening shortness of breath. The workup demonstrated a well-functioning MV prosthesis and normal LV function, but elevated filling pressures. After two months of diuresis, Mr. S continued to have NYHA Class IIIB symptoms with persistent Cpc-PH. He was subsequently started on ARNI, and two months later had complete resolution of his symptoms. Repeat evaluation showed normalization of pulmonary vascular resistance (PVR, see Table). <h3>Summary</h3> This report is the first to describe treatment of VHD-PH with ARNI along with invasive hemodynamic data showing successful reduction in PVR. In these two cases, treatment with ARNI led to reduction in not only mean pulmonary arterial pressures but also PVR. Future prospective trials are needed to evaluate role of ARNIs in treatment of VHD-PH.

The Negative Bidirectional Interaction Between Climate Change and the Prevalence and Care of Liver Disease: A Joint BSG, BASL, EASL, and AASLD Commentary

The Negative Bidirectional Interaction Between Climate Change and the Prevalence and Care of Liver Disease: A Joint BSG, BASL, EASL, and AASLD Commentary

Role of the Autonomic Nervous System in the Hemodynamic Response to Hyperinsulinemia-Implications for Obesity and Insulin Resistance.

Herein, we summarize recent advances which provide new insights into the role of the autonomic nervous system in the control of blood flow and blood pressure during hyperinsulinemia. We also highlight remaining gaps in knowledge as it pertains to the translation of findings to relevant human chronic conditions such as obesity, insulin resistance, and type 2 diabetes. Our findings in insulin-sensitive adults show that increases in muscle sympathetic nerve activity with hyperinsulinemia do not result in greater sympathetically mediated vasoconstriction in the peripheral circulation. Both an attenuation of α-adrenergic-receptor vasoconstriction and augmented β-adrenergic vasodilation in the setting of high insulin likely explain these findings. In the absence of an increase in sympathetically mediated restraint of peripheral vasodilation during hyperinsulinemia, blood pressure is supported by increases in cardiac output in insulin-sensitive individuals. We highlight a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase sympathetic nervous system activity and maintain blood pressure in insulin-sensitive adults. Whether these results translate to the insulin-resistant condition and implications for long-term cardiovascular regulation warrants further exploration.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Metabolic trade-offs favor regulated hypothermia and inhibit fever in immune-challenged chicks.

The febrile response to resist a pathogen is energetically expensive, while regulated hypothermia seems to preserve energy for vital functions. We hypothesized here that immune-challenged birds facing metabolic trade-offs (reduced energy supply/increased energy demand) favor a regulated hypothermic response at the expense of fever. To test this hypothesis, we compared 5day old broiler chicks exposed to fasting, cold (25°C), and fasting combined with cold with a control group fed under thermoneutral conditions (30°C). The chicks were injected with saline or with a high dose of endotoxin known to induce a biphasic thermal response composed of a drop in body temperature (Tb) followed by fever. Then Tb, oxygen consumption (metabolic rate), peripheral vasomotion (cutaneous heat exchange), breathing frequency (respiratory heat exchange) and huddling behavior (heat conservation indicator) were analyzed. Irrespective of metabolic trade-offs, chicks presented a transient regulated hypothermia in the first hour, which relied on a suppressed metabolic rate for all groups, increased breathing frequency for chicks fed/fasted at 30°C, and peripheral vasodilation in chicks fed/fasted at 25°C. Fever was observed only in chicks kept at thermoneutrality and was supported by peripheral vasoconstriction and huddling behavior. Fed and fasted chicks at 25°C completely eliminated fever despite the ability to increase metabolic rate for thermogenesis in the phase correspondent to fever when it was pharmacologically induced by 2,4-dinitrophenol. Our data suggest that increased competing demands affect chicks' response to an immune challenge, favoring regulated hypothermia to preserve energy while the high costs of fever to resist a pathogen are avoided.

Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation

Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O2 sensor and O2-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian Hbs, β-globin cysteine93 (βCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during O2 delivery. βCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting O2 normally. Here, we show that βCys93Ala mutant mice had reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion and that hypoxic vasodilation by RBCs was impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, βCys93Ala mutant mice showed marked impairment of hypoxic peripheral vasodilation and developed signs of pulmonary hypertension with age. Mutant mice also died prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low O2. Altogether, we identify a major role for RBC SNO in clinically relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle.

Multiple ulcerated lesions in a patient from Amazon, Brazil

Multiple ulcerated lesions in a patient from Amazon, Brazil

The Roles of Platelet-Activating Factor and Magnesium in Pathophysiology of Hypertension, Atherogenesis, Cardiovascular Disease, Stroke and Aging

Hypertension and atherosclerosis are debilitating diseases that affect millions each year. Long-term consequences include but are not limited to stroke, myocardial infarction, and kidney failure. Platelet-activating factor (PAF) is a proinflammatory mediator synthesized from a subclass of phosphatidylcholines that increases platelet activation, leukocyte adhesion, infiltration of macrophages, and intracellular lipid accumulation, thereby contributing to atherosclerosis. Magnesium, a key micronutrient and free radical scavenger, is a water-soluble mineral that regulates peripheral vasodilation and calcium, phosphate, and hydroxyapatite homeostasis. Magnesium’s antihypertensive ability stems from its role as a natural calcium antagonist and promoter of vasodilatory mediators, such as nitric oxide. Platelet-activating factor and magnesium share an inverse relationship, and elevated magnesium levels have been shown to have protective effects against plaque formation as well as antihypertensive and antiarrhythmic effects, all of which allow for healthier aging. The purpose of this literature review is to investigate the role of platelet-activating factor and magnesium in the pathophysiology of hypertension, atherosclerosis, cardiovascular disease, stroke, and aging. Since the pathophysiology of the platelet-activating factor biomolecule is underexplored, further research studies are warranted in order to navigate the putative signaling pathways involved in the cardioprotective effects of dietary magnesium as a natural anti-PAF agent.

Acute decompensated heart failure. What has changed in the clinical guidelines in 2021?

In September 2021, the European Society of Cardiology issued new guidelines on the management of patients with heart failure (HF). In the current version, experts have focused on the 4 most common variants: acute HF decompensation, acute pulmonary edema, cardiogenic shock, and isolated right ventricular failure. There has been a change in approaches to the initial management of patients with acute HF decompensation towards a decrease in the evidence-based use of peripheral vasodilators and a "return" to loop diuretics as the basis of treatment. This raises the question of monitoring the efficacy of diuretic therapy. The paper presents an algorithm proposed by the European Society of Cardiology.

Effect Study of Physiological changes of a Pregnant Woman

Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy isessential to optimize maternal and fetal health. During normal pregnancy, the renin–angiotensin system (RAS) plays avitally important role in salt balance and subsequent well-being of mother and fetus. In this balance, one must consider notonly the classical renal RAS but also that of the uteroplacental unit, where both maternal and fetal tissues contribute to thesignaling cascade. Many studies have shown that in normal pregnancy there is an increase in almost all of the componentsof the RAS. In derangements of pregnancy this delicate equilibrium can become unbalanced. Preeclampsia is one suchcase. It is a disorder of pregnancy characterized by hypertension, proteinuria and placental abnormalities associated withshallow trophoblast invasion and impaired spiral artery remodeling. Changes in the cardiovascular system in pregnancyare profound and begin early in pregnancy, such that by eight weeks’ gestation, the cardiac output has already increasedby 20%. The primary event is probably peripheral vasodilatation. This is mediated by endothelium-dependent factors,including nitric oxide synthesis, upregulated by oestradiol and possibly vasodilatory prostaglandins (PGI2). There is asignificant increase in oxygen demand during normal pregnancy. This is due to a 15% increase in the metabolic rate anda 20% increased consumption of oxygen.

Irisin relaxes rat thoracic aorta through inhibiting signaling pathways implicating protein kinase C.

Irisin, a newly identified exercise-derived myokine, has been found involved in a peripheral vasodilator effect. However, little is known regarding the potential vascular activity of irisin, and the mechanisms underlying its effects on vascular smooth muscle have not been fully elucidated. This study was aimed to investigate the effects of irisin on vascular smooth muscle contractility in rat thoracic aorta, and the hypothesis that protein kinase C (PKC) may have a role in these effects. Isometric contraction-relaxation responses of thoracic aorta rings were measured with an isolated organ bath model. The steady contraction was induced with 10 µM phenylephrine (PHE), and then the concentration-dependent responses of irisin (0.001-1 µM) were examined. The time-matched vehicle control (double distilled water) group was also formed. To evaluate the role of PKC, endothelium-intact thoracic aorta rings were incubated with 150 nM bisindolylmaleimide I (BIM I) for 20 min before the addition of 10 µM PHE and irisin. Also, a vehicle control group was formed for dimethyl sulfoxide (DMSO). Irisin exerted the vasorelaxant effects at concentrations of 0.01, 0.1, and 1 µM compared to the control group (p < 0.001). Besides, PKC inhibitor BIM I incubation significantly inhibited the relaxation responses induced by varying concentrations of irisin (p: 0.000 for 0.01 µM; p: 0.000 for 0.1 µM; p: 0.000 for 1 µM). However, DMSO, a solvent of BIM I, did not modulate the relaxant effects of irisin (p > 0.05). In conclusion, physiological findings were obtained regarding the functional relaxing effects of irisin in rat thoracic aorta. The findings demonstrated that irisin induces relaxation responses in endothelium-intact thoracic aorta rings in a concentration-dependent manner. Furthermore, this study is the first to report that irisin-induced relaxation responses are regulated probably via activating signaling pathways implicating PKC.