Systemic Vascular Resistance Responses Research Articles

Pathophysiologic Vasodilation in Cardiogenic Shock and Its Impact on Mortality.

Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm-5 (interquartile range, 870-1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0-0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm-5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P=0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P<0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P=0.003). Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm-5, high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.

#536 Dedicated patient optimization program delivers effective complex intervention improving the lives of vulnerable HD patients

Abstract Background and Aims Hemodialysis (HD) delivery is failing many patients due to a of lack of available evidence/dialysis-based interventions (previously only studied as single interventions in isolation) to improve outcomes; and the industrialization of institutional-based HD imposing a ‘one size fits all’ approach. To respond to the needs of the most vulnerable patients we have instituted a patient optimization program (POP) to support our Renal Program, fully leveraging our research level assessment tools to provide an individualized appreciation of challenges before delivering an equally individualized complex intervention. The aim was to improve subjective experience [symptoms/health related quality of life (HRQoL) measures] and objective evidence of HD related harm. Method Patients who had suboptimal tolerability to HD were identified and referred by the clinical team (after best efforts to address concern as part of standard care). To understand the patients’ individual challenges, a series of physiological, hemodynamic, and HRQoL assessments were completed. Based on these findings, a series of complex foundational (common to all patients treated) and patient specific interventions were applied, and impact rigorously evaluated. HRQoL/symptoms were measured using the dynamic patient reported outcome measurement tool LEVIL [2-4 weeks leading up to the program (baseline) and continually thereafter]. Comprehensive physiological assessment period was two weeks in length (six HD treatments) and included continuous beat to beat hemodynamic monitoring, intradialytic echocardiography (assess myocardial stunning) and objective volume assessment using ultrasound and bioimpedance. The first session was delivered mirroring routine prescription (establish primary response), subsequent treatments were delivered implementing a variety of foundational, patient/disease specific interventions in a staged manner. Results To date 13 patients have completed the program, referred for a variety of reasons [refractory hypotension (5/13), intradialytic hypotension (2/13) and poor HRQoL [symptoms—cramping, headache, pruritus, insomnia (8/13)]. Complexes of challenges were present in 9/13. All patients had multiple components of dialysis altered. POP was associated with a marked improvement in a range of subjective and objective outcomes. Subjectively, HRQoL improved by 10% [composite LEVIL scores 69.5 ± 15.5 at baseline, 76.5 ± 17 after POP participation (p 0.03)], energy by 18% (64.7 ± 16.2, 76.5 ± 6.4, p 0.01), general wellbeing by 11% (76.5 ± 6.6, 85.2 ± 4.2, p 0.02), and post-dialysis recovery improved from 13.3 ± 16.1 hours to only 2 ± 1.9 hours (p 0.02). Objectively, intradialytic weight gain decreased by 36% (2333.3 ± 1151.8 ml at baseline to 1483.3 ± 591.3 ml, p 0.03), systolic blood pressure improved by 12% [94.9 ± 28.5 mmHg at baseline to 106.2 ± 30 mmHg post optimization p &amp;lt; 0.0001 (despite midodrine being discontinued in 8/13 patients previously dependent on it)]. Tolerability of HD improved (cardiac output 6.4 ± 0.1, 6.5 ± 1, p 0.002 and intradialytic systemic vascular resistance response 15 ± 23.6% at baseline to 48.7 ± 53%, p &amp;lt; 0.0001). Improvement in hemodynamic tolerability led to a reduction in HD induced myocardial stunning larger than reported with any previously applied single intervention; regional wall motion abnormality fell from 5.6 ± 2.4 at baseline (severe stunning) to only 1.2 ± 1.3 (p 0.02) over the two-week program. 2/13 patients who had previously been declined transplantation were accepted and need to repatriate from satellite facilities to in-centre was avoided. Conclusion For the first time, we have created an opportunity for the most challenging patients who have failed conventional best efforts. We have successfully demonstrated the impact of delivering a complex intervention (with a degree of treatment personalization) targeting physiological failure in the most vulnerable HD patients. POP improved HRQoL (principal impact measure), hemodynamic stability and treatment tolerability. Having demonstrated the effectiveness of this approach, we now focus on solutions to up-scale this success.

Hormonal Control of Blood Viscosity.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities.Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus.By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

The ventilatory component of the muscle metaboreflex is overstimulated in transthyretin cardiac amyloidosis patients with poor aerobic capacity.

Background: The exercise pressor reflex, i.e., metabo- and mechano-reflex, partially regulates the control of ventilation and cardiovascular function during exercise. Abnormal exercise pressor reflex response has been associated with exaggerated ventilatory drive, sympathovagal imbalance and exercise limitation in chronic heart failure patients. Whether metaboreflex is over-activated and participate to poor aerobic capacity in patients with hereditary transthyretin cardiac amyloidosis (CA-TTR) is unknown. Methods: Twenty-two CA-TTR patients (aged 76 ± 7, 68% male) with the V122I (p.Val142Ile) transthyretin underwent a thorough evaluation including heart rate variability metrics, electrochemical skin conductance (ESC), physical function cardiopulmonary exercise testing, and muscle metaboreflex assessment. Eleven control subjects were chosen for muscle metaboreflex assessment. Results: Age-matched controls (n = 11) and CA-TTR patients (n = 22) had similar metaboreflex sensitivity for heart rate, stroke volume, cardiac index and mean systemic arterial pressure. Compared with age-matched controls, metaboreflex sensitivity for systemic vascular resistance (-18.64% ± 6.91% vs 3.14% ± 23.35%) and minute-ventilation responses (-9.65% ± 14.83% vs 11.84% ± 23.1%) was markedly increased in CA-TTR patients. Values of ESC displayed positive correlations with stroke volume (r = 0.53, p = 0.011) and cardiac index (r = 0.51, p = 0.015) components of metaboreflex sensitivity, an inverse correlation with systemic vascular resistance (r = -0.55, p = 0.008) and a trend with mean arterial (r = -0.42, p = 0.052) components of metaboreflex sensitivity. Peak aerobic capacity (peak VO2%) displayed an inverse correlation with the ventilation component of metaboreflex sensitivity (r = -0.62, p = 0.015). Conclusion: Consistent with the "muscle hypothesis" in heart failure, it is proposed that deterioration of skeletal muscle function in hereditary CA-TTR patients may activate muscle metaboreflex, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and overall sympathetic activation.

Cholinergic‐mediated Circulatory Responses at the Onset of Isometric Exercise: Does Sex Matter?

IntroductionWe have shown that handgrip exercise evokes an initial decrease in systemic vascular resistance (SVR), which was abolished by cholinergic blockade (glycopyrrolate) and, thereby, augmented the blood pressure (BP) response. These findings suggest that a cholinergic mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans. Noteworthy, this previous study included men only, and was not designed to investigate the potential existence of sex‐related differences in immediate BP and circulatory responses evoked at the exercise onset. Given this, the aim of this study was to test the hypothesis that women present an attenuated fall in SVR and increased pressor response compared to men at the onset of isometric handgrip exercise due to a blunted cholinergic vasodilation.MethodsTen healthy men (aged 21 ± 1 year) and 10 women (aged 24 ± 1 year) were recruited. Women were non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. Participants performed 20s bout of isometric handgrip exercise at 40% of maximal voluntary contraction. Beat‐to‐beat heart rate (HR) (ECG) and mean BP (finger photopletysmography) were continuously measured. Beat‐to‐beat stroke volume (SV) was obtained with the Modelflow method and matched with HR to estimate cardiac output (CO) and SVR. The exercise responses were expressed as a change from 10s immediately before the onset of voluntary contraction.ResultsThe BP response pattern appeared to be different between men and women at the onset of isometric exercise. While men presented a typical exercise‐evoked biphasic BP response (3s: Δ2 ± 2 mmHg; 10s: Δ1 ± 1 mmHg; 20s: Δ5 ± 3 mmHg), women showed a progressive increase in mean BP (3s: Δ1 ± 1 mmHg; 10s; Δ3 ± 1 mmHg; 20s: Δ6 ± 1 mmHg; P=0.681). Men demonstrated a decrease in SVR at 3s (Δ‐0.9 ± 0.3 mmHg.L‐1.min), 10s (Δ ‐1.6 ± 0.4 mmHg.L‐1.min) and 20s (Δ‐1.9 ± 0.7 mmHg.L‐1.min) following the exercise onset, and these responses tended to be attenuated in women (3s: Δ‐0.3 ± 0.3 mmHg.L‐1.min; 10s: Δ‐1.2 ± 0.4 mmHg.L‐1.min; 20s: Δ‐0.6 ± 0.5 mmHg.L‐1.min; P=0.131). There were no sex differences in HR, SV and CO responses to exercise.ConclusionThese findings suggest a lack of sex differences in immediate BP and circulatory responses at the onset of isometric handgrip exercise, indicative of similar cholinergic‐mediated vasodilation in skeletal muscle between men and women.

342 Cardiorespiratory fitness and systemic vascular resistance: oxygen pressure as a novel marker of peripheral vascular response during cardiopulmonary exercise testing

Abstract Aims The key role of systemic vascular resistance (SVR) in cardiovascular performance during exercise has been invasively demonstrated, however no data have been non-invasively obtained by analysing SVR response using cardiopulmonary exercise testing (CPET). To investigate the relationship between SVR at peak, maximum oxygen uptake (VO2 peak), and its determinants using CPET. Methods and results 1130 consecutive subjects were enrolled; according to physiology, SVR was determined as the ratio between mean arterial pressure (MAP) and cardiac output (CO). A novel parameter, named oxygen pressure (MAP peak/VO2 peak) was also created. Mean age was 61 ± 12 years and male gender was prevalent (61%); 66% of patients had arterial hypertension, 74% dyslipidaemia, 19% diabetes, 20% had smoking habit, and 26% previous history of cardiovascular (CV) disease. Significant inverse correlations between SVR peak and VO2/kg peak (P &amp;lt; 0.001), oxygen pulse (P &amp;lt; 0.001), CV efficiency (P &amp;lt; 0.001), chronotropic response (P &amp;lt; 0.001), and oxygen uptake exaction slope (P &amp;lt; 0.001) were found. Moreover, positive correlation between SVR peak and VE/VCO2 slope (P &amp;lt; 0.001) was observed. After multivariate analysis, the inverse correlation between peak SVR and peak VO2 remained significant (P &amp;lt; 0.001). Similar results were found considering oxygen pressure. Conclusions Low values of SVR at peak exercise, non-invasively evaluated with CPET, are associated with high levels of cardiorespiratory fitness. Oxygen pressure may represent a novel and simple CPET marker of peripheral vascular response to exercise, thereby representing a promising field of research in exercise medicine.

Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients

Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

To investigate the cause of salt sensitivity in a normotensive animal model, we treated rats with a low-dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se or induce kidney fibrosis. A high salt diet increased the circulating blood volume both in L-NAME-treated and nontreated animals for the first 24 hours. Thereafter, the blood volume increase persisted only in the L-NAME-treated rats. Blood pressure was higher in the L-NAME-treated group from the start of high salt diet exposure. Within the first 24 hours of salt loading, the L-NAME treated animals failed to show vasodilation and maintained high systemic vascular resistance in response to blood volume expansion. After four weeks on the high salt diet, the slope of the pressure-natriuresis curve was blunted in the L-NAME-treated group. An increase in natriuresis was observed after treatment with hydrochlorothiazide, but not amiloride, a change observed in parallel with increased phosphorylated sodium-chloride cotransporter (NCC). In contrast, a change in blood pressure was not observed in L-NAME-treated NCC-deficient mice fed a high salt diet. Moreover, direct L-NAME-induced NCC activation was demonstrated in cells of the mouse distal convoluted tubule. The vasodilatator, sodium nitroprusside, downregulated phosphorylated NCC expression. The effect of L-NAME on phosphorylated NCC was blocked by both the SPAK inhibitor STOCK2S-26016 and the superoxide dismutase mimetic TEMPO which also attenuated salt-induced hypertension. These results suggest that the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature and that maintaining blood pressure could result in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. Thus, even slightly impaired nitric oxide production may be important in salt sensitivity regulation in healthy rodents.

Combined influence of inspiratory loading and locomotor subsystolic cuff inflation on cardiovascular responses during submaximal exercise.

It is unknown if simultaneous stimulation of the respiratory and locomotor muscle afferents via inspiratory loading (IL) and locomotor subsystolic cuff inflation (CUFF) influences the cardiovascular responses during exercise. We hypothesized that combined IL and CUFF (IL + CUFF) will result in greater increases in blood pressure (MAP) and systemic vascular resistance (SVR) than IL and CUFF alone during exercise. Eight adults (6 males/2 females) were enrolled and performed four 10-min bouts of constant-load cycling eliciting 40% maximal oxygen uptake on a single day. For each exercise bout, the first 5 min consisted of spontaneous breathing. The second 5 min consisted of voluntary hyperventilation (i.e., breathing frequency of 40 breaths/min) with IL (30% maximum inspiratory pressure), CUFF (80 mmHg), IL + CUFF, or no intervention (CTL) in randomized order. During exercise, cardiac output and MAP were determined via open-circuit acetylene wash-in and manual sphygmomanometry, respectively, and SVR was calculated. Across CTL, IL, CUFF, and IL + CUFF, MAP was greater with each condition (CTL: 97 ± 14; IL: 106 ± 13; CUFF: 114 ± 14; IL + CUFF: 119 ± 15 mmHg, all P < 0.02). Furthermore, SVR was greater with IL + CUFF compared with IL, CUFF, and CTL (CTL: 6.6 ± 1.1; IL: 7.5 ± 1.4; CUFF: 7.5 ± 1.3; IL + CUFF: 8.2 ± 1.4 mmHg·L-1·min-1, all P < 0.02). Cardiac output was not different across conditions (CTL: 15.2 ± 3.8; IL: 14.8 ± 3.7; CUFF: 15.6 ± 3.5; IL + CUFF: 14.7 ± 4.3 L/min, all P > 0.05). These data demonstrate that simultaneous stimulation of respiratory and locomotor muscle afferent feedback results in additive MAP and SVR responses than IL and CUFF alone during submaximal exercise. These findings have important clinical implications for populations with exaggerated locomotor and respiratory muscle reflex feedbacks.NEW & NOTEWORTHY Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.

No effect of anti‐hypertensive treatment during the metaboreflex in patients with essential hypertension

In healthy subjects (HS), when the muscle metaboreflex (MM) is activated, the target mean blood pressure (MBP) is reached thanks to cardiac output (CO) increments, whilst systemic vascular resistance (SVR) plays a minor role 1. Differently, in essential hypertension (EHT) hemodynamics during the MM has been often reported to be dys‐regulated, with exaggerated SVR response (i.e. arteriolar vasoconstriction) and reduced CO 2. We tested the hypothesis that standard anti‐hypertensive treatment could improve this abnormal hemodynamics. 20 patients in pharmacological treatment for EHT (10 females; age 54.5±10.4 yrs, time since diagnosis 8.5±6.9 yrs) participated in this study together with a control group of 20 age‐matched HS. At baseline (BAS), they underwent randomly assigned the following protocol to study the MM activity: 1) post‐exercise muscle ischemia (PEMI), and 2) control exercise recovery CER) test. Exercise was dynamic handgrip performed at 30% of the maximum previously assessed. The EHT group performed again the test at least 7 days later (interval 7–15 days) after pharmacological wash‐out (WHT). Response to the MM for each cardiovascular parameter was assessed as PEMI minus CER level. Hemodynamic variables were evaluated by impedance cardiography. Results demonstrated that in EHT, SVR response did not change at the BAS and at the WHT (338.0±452.7 vs. 371.8±465.3 dynes•s‐1•cm‐5 at BAS and at WHT respectively). Moreover, EHT showed higher SVR response than HS (20.9±399.6 dynes•s‐1•cm‐5, p&lt;0.05 vs. both the BAS and the WHT test). However, the MBP response was similar between groups and conditions. Likewise CO was not different between groups. It was concluded that the anti‐hypertensive treatment was not able to counteract the arteriolar vasoconstriction and the increased SVR response experienced by ETH patients during the MM. Further study is warranted to better understand what causes the hemodynamic abnormalities of EHT patients during the MM activation.Support or Funding InformationThis study was supported by the University of Cagliari and the Italian Ministry of Scientific Research.

METABOREFLEX ACTIVITY IN HEART FAILURE WITH REDUCED AND PRESERVED EJECTION FRACTION

IntroductionChronic heart failure (CHF) is a syndrome characterized by reduced cardiac output (CO) unable to meet metabolic demands of active tissues. The reduced (HFrEF) or preserved ejection fraction (HFpEF) identifies the systolic and diastolic HF respectively. Evidence has demonstrated that metabolic reflex coming from skeletal muscle evokes cardiovascular adjustments during exercise. Hemodynamic response to metaboreflex activation is defined as a rise in mean arterial blood pressure (MAP) achieved by an increase in systemic vascular resistance (SVR) and/or by an increase in CO. In healthy individuals, the metaboreflex‐induced increase in blood pressure mainly depends on CO increment. The aim of the present study was to assess cardiovascular adjustments during metaboreflex activation in both kinds of CHF patients compared to a control group of healthy individuals (CTL).MethodsThree groups of age‐matched subjects were studied: 1) 12 males patients diagnosed with HFrEF; 2) 8 males patients with diagnosed HFpEF; 3) 12 healthy individuals (CTL). All participants underwent a general medical examination, an incremental exercise test on a cycle ergometer to test their physical capacity, and a metaboreflex activation protocol consisting in a post exercise muscle ischemia (PEMI) and in a control exercise recovery (CER) session. All hemodynamic parameters were measured non‐invasively by impedance cardiography.ResultsStatistical analysis showed no differences in heart rate (HR) response among groups. Stroke volume (SV) and CO responses were not significantly different between the two groups of HF patients. SV and CO responses were significantly higher in the CTL than in both the HFrEF and the HFpEF group. SVR response was significantly higher in the HFrEF as compared to the CTL group, while no differences existed between the CTL and the HFpEF. MAP response to PEMI was not different among groups. Ventricular Filling Rate (VFR, a measure of diastolic function) response was significantly higher in CTL group in comparison with the HFrEF and the HFpEF groups. Ventricular Emptying Rate (VER, a measure of systolic function) response was significantly higher in CTL group as compared to the two groups of patients.ConclusionNotwithstanding the described reduced capacity to enhance CO, the MAP response was not different among groups. This indicates that the possibility to reach an effective MAP pressure was unaltered in both groups of patients with CHF. This was likely the consequence of an exaggerated vasoconstriction due to a sympathetic overdrive in both groups of CHF patients. These findings are in good agreement with previous research dealing with HFrEF and HFpEF, which demonstrated the blood pressure rise during the metaboreflex is mainly achieved by a vasoconstriction‐mediated rather than a flow‐mediated mechanism. Of note the SVR increase was more accentuated in the HFrEF than in the HFpEF group, and this phenomenon suggests that the cardiovascular impairment was more pronounced in the former than in the latter group of patients.

The Effect of Subsystolic Regional Circulatory Occlusion on Blood Pressure and Systemic Vascular Resistance in Men and Women during Exercise

IntroductionThe exercise pressor reflex contributes to cardiovascular regulation during exercise. The primary components of the exercise pressor reflex response are the mechanically and metabolically sensitive skeletal muscle afferents (group III and IV, respectively). Experimentally, subsystolic regional circulatory occlusion (SubRCO) leads to venous distention, stimulating primarily group III afferents, thereby augmenting the exercise pressor reflex. Previous studies have reported sex differences in the metaboreflex induced exercise pressor reflex induced cardiovascular responses. Specifically, pre‐menopausal women, compared to age‐matched men, were found to have attenuated cardiovascular responses with mechanoreflex stimulation. However, it is unclear if sex differences are also present in the cardiovascular responses during exercise with locomotor limb venous distention. Therefore, the purpose of this study was to determine the influence of SubRCO during submaximal exercise in men and women. We hypothesized that women will have attenuated increases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) than men during exercise with SubRCO.MethodsTwelve men and thirteen women completed two study visits (Age: M: 30±6vs. W: 27±8yrs, p&gt;0.05; BMI: M: 25.4±3.6 vs. W: 22±3 kg/m2, p&lt;0.05). The first visit consisted of a peak exercise ergometry test. The second visit consisted of constant‐load cycle ergometry at 30% peak workload with different SubRCO pressures via bilateral upper thigh pressure cuffs. The cuffs remained uninflated (0 mmHg) (CTL) during the first three min of exercise, then were intermittently inflated to 20, 40, 60, 80, or 100 mmHg for two minutes (randomized order). Each inflation period was followed by a 2minute deflation period where the participant continued to exercise. Cardiacoutput (Q) and MAP were measured via continuous hemodynamic photoplethysmography and systemic vascular resistance (SVR) was calculated. Data were reported as delta changes from CTL.ResultsCompared to 0 mmHg, MAP increased with SubRCO inflation pressures of 60, 80, and 100mmHg in men and women during submaximal exercise (all, p&lt;0.05); however, no differences were present between groups (60 mmHg: M: 6.2±4.2 vs. W: 8.0±5.2; 80mmHg: M: 11.6±5.5 vs. W: 15.1±4.8; 100 mmHg: M: 18.2±6.6 vs. W: 20.5±7.2 mmHg(all, p&gt;0.05)). Similarly, SVR increased with cuff inflation pressures of60, 80, and 100 mmHg compared to 0 mmHg in men and women (p&lt;0.05), while no differences existed between groups (60 mmHg: M: 0.3±0.4 vs W: 0.4±0.5;80 mmHg: M: 0.9±0.5 vs W: 1.1± 0.9; 100 mmHg M: 1.3±0.8vs W: 1.5±0.8mmHg/L/min (all, p&gt;0.05)). In contrast, Q did not change with cuff inflation pressures of 20, 40, 60, 80, or100 mmHg compared to 0 mmHg in men or women during submaximal exercise(p&gt;0.05).ConclusionIn contrast to our hypothesis, the MAP and SVR responses were not different between men and women with SubRCO during submaximal exercise. Our findings suggest that sex differences are not present in the cardiovascular response to low‐intensity constant‐load exercise with stimulation of the exercise pressor reflex via lower limb venous distention.

INTEGRATED EFFECTS OF NORMOBARIC HYPOXIA AND METABOREFLEX ACTIVATION ON HEMODYNAMICS

IntroductionBoth metaboreflex activity and hypoxia affect hemodynamics. In particular, metaboreflex induces an augmentation in stroke volume (SV), systemic vascular resistance (SVR), and blood pressure (BP) by activating the sympathetic nervous system (SNS). In contrast, hypoxia produces a heart rate (HR)‐mediated increase in cardiac output (CO), while its effect on SVR is variable as it increases SNS activity but, at the same time, it triggers nitric oxide (NO) production in the endothelium, thus inducing venous and arteriolar dilation. Since studies on the possible interaction between metaboreflex and hypoxia are still lacking, our investigation aimed to study their combined effects on hemodynamics.Methods11 male subjects underwent a preliminary cardiopulmonary exercise test (CPET) on a cycle ergometer to assess their aerobic fitness. Then, a metaboreflex activation protocol in normoxia and normobaric hypoxia (fraction of inspired oxygen – FiO2 – of 13.5%) was conducted on separate days. Hypoxia was induced using a hypoxic gas generator (Everest Summit II Generator, Hypoxico, USA) connected to the subjects by a facemask. The metaboreflex activation protocol consisted of two randomly assigned sessions: one of post‐exercise muscle ischemia (PEMI) and one of control exercise recovery (CER). PEMI comprised a 3‐minute exercise bout pedaling at 30% of the maximum workload reached during the CPET followed by 3 minutes of vascular occlusion using an inflatable thigh cuff to stimulate the metaboreflex. CER was similar, but no occlusion was applied after the exercise session. SV, HR, CO, ventricular filling rate (VFR), and ventricular ejection rate (VER) were measured through impedance cardiography while mean blood pressure (MBP) was assessed using manual sphygmomanometer. SVR was calculated indirectly from CO and MBP according to Poiseuille’s law. Near‐infrared spectroscopy was employed to measure cerebral oxygenation (COX) and peripheral hemoglobin saturation (SPO2) to control the level of tissue hypoxia. Two‐way ANOVA and paired sample t‐test were utilized when appropriate.ResultsCO was increased during metaboreflex activation in normoxia (p= 0.013) but not in hypoxia. SV, CO, and VFR responses to metaboreflex (measured as the difference PEMI‐CER at the third minute after exercise) were reduced when the hypoxic stimulus was applied (p=0.02; p=0.02; p=0.003 respectively). Moreover, SVR response showed a nearly significant (p=0.07) increase in hypoxia, with MBP response being unchanged. COX and SPO2 confirmed that the hypoxic stimulus was effective.DiscussionResults demonstrated that hypoxia impaired the hemodynamic response to metaboreflex. Specifically, SV was reduced during metaboreflex in hypoxia because of a reduction in preload as a consequence of two mechanisms: 1) a reduction in venous return probably induced by NO‐mediated vasodilation of the venous bed; 2) an increase in right ventricle afterload likely produced by the pulmonary arterial system vasoconstriction. Of note, baroreflex successfully defended MBP response despite the reduced CO during hypoxia.

The Role of Blood Viscosity in Infectious Diseases.

Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood.

Hemodynamic abnormalities during muscle metaboreflex activation in patients with type 2 diabetes mellitus.

Metaboreflex is a reflex triggered during exercise or postexercise muscle ischemia (PEMI) by metaboreceptor stimulation. Typical features of metaboreflex are increased cardiac output (CO) and blood pressure. Patients suffering from metabolic syndrome display hemodynamic abnormalities, with an exaggerated systemic vascular resistance (SVR) and reduced CO response during PEMI-induced metaboreflex. Whether patients with type 2 diabetes mellitus (DM2) have similar hemodynamic abnormalities is unknown. Here we contrast the hemodynamic response to PEMI in 14 patients suffering from DM2 (age 62.7 ± 8.3 yr) and in 15 age-matched controls (CTLs). All participants underwent a control exercise recovery reference test and a PEMI test to obtain the metaboreflex response. Central hemodynamics were evaluated by unbiased operator-independent impedance cardiography. Although the blood pressure response to PEMI was not significantly different between the groups, we found that the SVR and CO responses were reversed in patients with DM2 as compared with the CTLs (SVR: 392.5 ± 549.6 and -14.8 ± 258.9 dyn·s-1·cm-5; CO: -0.25 ± 0.63 and 0.46 ± 0.50 l/m, respectively, in DM2 and in CTL groups, respectively; P < 0.05 for both). Of note, stroke volume (SV) increased during PEMI in the CTL group only. Failure to increase SV and CO was the consequence of reduced venous return, impaired cardiac performance, and augmented afterload in patients with DM2. We conclude that patients with DM2 have an exaggerated vasoconstriction in response to metaboreflex activation not accompanied by a concomitant increase in heart performance. Therefore, in these patients, blood pressure response to the metaboreflex relies more on SVR increases rather than on increases in SV and CO. NEW & NOTEWORTHY The main new finding of the present investigation is that subjects with type 2 diabetes mellitus have an exaggerated vasoconstriction in response to metaboreflex activation. In these patients, blood pressure response to the metaboreflex relies more on systemic vascular resistance than on cardiac output increments.

Muscle metaboreflex activity after an acute session of exercise under hypoxia

In healthy subjects, when the muscle metaboreflex (MM) is activated, mean blood pressure (MBP) increases because of a sympathetic‐induced increase in both systemic vascular resistance (SVR) and cardiac output (CO)1. Acute hypoxia vasodilation has been often reported despite the increased sympathetic tone2. We hypothesized that a single session of exercise under normobaric hypoxia (ENH) resulted in an attenuation of the MBP increment during the muscle metaboreflex activated immediately after the ENH session. 10 well trained healthy male subjects (age 34.2±11.7 yrs) participated in this study. In separate days they underwent, randomly assigned, three exercise sessions consisting of 10 min pedaling at a workload corresponding to 80% of anaerobic threshold previously assessed. In one session (TEST21%) subjects breathed normoxic air (O2 21%), in the other two tests they breathed hypoxic air with O2 concentration of 16% (TEST16%) or 13% (TEST13%) respectively. Immediately after each exercise session they underwent randomly assigned the following protocol: 1) muscle metaboreflex activation obtained by the post‐exercise muscle ischemia (PEMI) method, and 2) control exercise recovery (CER) test. Response to the metaboreflex for each cardiovascular parameter was assessed as PEMI minus CER level. Hemodynamic parameters were evaluated by impedance cardiography. Results show that SVR response was reduced during the MM after the TST13% with respect to the other two tests (−46.5±394.2 vs. +108.9±256.3 and +213.6±228.8 dynes•s‐1•cm‐5 respectively, p&lt;0.05). However, the MBP response was similar between conditions. This because of an increased CO response which occurred during TEST13% in comparison with TEST21% and TEST16% (+421.3±545 vs. +63.2±322.9 and +128.3±238.6 ml respectively, p&lt;0.05). It was concluded that an acute session of exercise under hypoxia is able to reduce the capacity to vasoconstrict the vascular bed during the metaboreflex activation obtained by PEMI. However, mechanisms controlling cardiovascular responses successfully defended MBP response by increasing CO which compensated for the reduced SVR increment.Support or Funding InformationThis study was supported by the University of Cagliari and the Italian Ministry of Scientific Research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Occurrence of cardiac output decrease (via stroke volume) is more pronounced in women than in men during prolonged dry static apnea.

Little is known about sex differences in autonomic cardiovascular regulation of the diving response, and the few available studies of these differences were conducted on subjects with limited or no diving experience. We examined the influence of sex on hemodynamics during dry static apnea (SA) in eight male and eight female elite divers matched for their breath hold (BH) ability. Hemodynamics was assessed by means of simultaneous echocardiography and impedance cardiography measurements, and arterial pressure and oxygen saturation ([Formula: see text]) were also collected. In the first quarter (AP25%) and half (AP50%) of apnea duration cardiac output (CO) showed a more rapid and intense decrease in women than in men (-43% vs. -17% during AP25% and -40% vs. -19% during AP50%, respectively, P < 0.05). At the same time points, systemic vascular resistance (SVR) increased more in women than in men (+22% vs. +100% at AP25% and +48% vs. +107% at AP50%, respectively, P < 0.05). [Formula: see text] progressively declined in both groups, but men showed a more pronounced decrease than women at the end of apneas (-13% vs. -5%, respectively, P < 0.05). In men the higher the body surface area values the longer the apnea, while in women the higher the SVR response the longer the apnea. In elite female divers, the magnitude of CO decrease during dry SA was larger than in male divers. The capacities to store oxygen and to reduce O2 consumption play a pivotal role in BH performance, but their extent seems to be different in the sexes. NEW & NOTEWORTHY This is the first study in which the influence of sex on hemodynamics during dry static apnea has been investigated in two groups of elite divers matched for their breath hold ability. We also show the correlation between the performances obtained by divers during a real competition and their anthropometric, respiratory, and cardiovascular characteristics.

OP.7B.01] MASKED HYPERTENSIVES EXHIBIT AN EXAGGERATED BLOOD PRESSURE RESPONSE DURING HANDGRIP EXERCISE SIMILAR TO THAT IN HYPERTENSIVE INDIVIDUALS

Objective: Masked hypertension has been associated with increased risk for target organ damage and cardiovascular disease. Recent evidence indicate that hypertensive individuals exhibit exaggerated blood pressure (BP) response during exercise and delayed recovery, linked to excessive sympathetic stimulation and an overactive exercise pressor reflex. Whether individuals with masked hypertension (masked-HYP) also exhibit exaggerated BP and systemic vascular resistance (SVR) responses as true hypertensives (true-HYP) during exercise has not been investigated. Therefore, the aim of this study was to evaluate the cardiovascular responses during handgrip exercise and recovery in masked-HYP, true-HYP, and normotensive (NORMO) individuals. Design and method: Eighty six individuals participated in the present study: healthy-NORMO (n = 28), masked-HYP (n = 27), and true-HYP (n = 31). All hypertensive participants were newly diagnosed, untreated, with no other known cardiovascular disease. Following a complete history, physical examination, and blood testing, office and ambulatory BP were measured in order to determine their hypertensive status. All participants underwent an exercise protocol, consisting of a 3-min rest (baseline), a 3-min handgrip exercise at 30% maximal voluntary contraction (MVC), and a 3-min recovery. Beat-by-beat BP and heart rate (HR) were continuously assessed via photoplethysmography (Finapress) throughout the protocol and SVR was calculated. Results: There were no differences among the three groups in age, smoking status, body mass index, fasting blood glucose, lipid profile, and MVC. Masked-HYP exhibited similar baseline BP to NORMO, however, during HG-exercise, masked-HYP exhibited a markedly greater (p < 0.05) systolic/diastolic BP response compared with NORMO (174.8 ± 13.5/98.5 ± 7.0 vs. 159.2 ± 15.7/91.3 ± 9.2 mmHg, respectively) and similar BP responses to true-HYP (181.4 ± 14.5/101.8 ± 9.5 mmHg). In addition, during exercise, masked-HYP exhibited a significant increase in SVR (p < 0.05), similar to that observed in true-HYP, whereas no significant increase in SVR was observed in NORMO. During the 3-min post-exercise period, BP in masked-HYP declined and returned to values comparable to those in NORMO (p = 0.32). Conclusions: This is the first study to show that during isometric exercise, masked-HYP exhibit exaggerated BP and SVR responses, suggesting an overactive exercise pressor reflex in masked hypertension. The cardiovascular responses during exercise in masked-HYP are similar to those in true-HYP.

Effects of Six Months Training on Physical Capacity and Metaboreflex Activity in Patients with Multiple Sclerosis.

Patients with multiple sclerosis (MS) have an increased systemic vascular resistance (SVR) response during the metaboreflex. It has been hypothesized that this is the consequence of a sedentary lifestyle secondary to MS. The purpose of this study was to discover whether a 6-month training program could reverse this hemodynamic dysregulation. Patients were randomly assigned to one of the following two groups: the intervention group (MSIT, n = 11), who followed an adapted training program; and the control group (MSCTL, n = 10), who continued with their sedentary lifestyle. Cardiovascular response during the metaboreflex was evaluated using the post-exercise muscle ischemia (PEMI) method and during a control exercise recovery (CER) test. The difference in hemodynamic variables such as stroke volume (SV), cardiac output (CO), and SVR between the PEMI and the CER tests was calculated to assess the metaboreflex response. Moreover, physical capacity was measured during a cardiopulmonary test till exhaustion. All tests were repeated after 3 and 6 months (T3 and T6, respectively) from the beginning of the study. The main result was that the MSIT group substantially improved parameters related to physical capacity (+5.31 ± 5.12 ml·min−1/kg in maximal oxygen uptake at T6) in comparison with the MSCTL group (−0.97 ± 4.89 ml·min−1/kg at T6; group effect: p = 0.0004). However, none of the hemodynamic variables changed in response to the metaboreflex activation. It was concluded that a 6-month period of adapted physical training was unable to reverse the hemodynamic dys-regulation in response to metaboreflex activation in these patients.

Initial orthostatic hypotension in teenagers and young adults.

ObjectiveTo assess: (1) the frequency of an abnormally large fall in blood pressure (BP) upon standing from supine in patients with initial orthostatic hypotension (IOH); (2) the underlying hemodynamic mechanisms of this fall in BP upon standing from supine and from squatting.MethodsIn a retrospective study of 371 patients (≤30 years) visiting the syncope unit, the hemodynamic response to standing and squatting were studied in 26 patients who were diagnosed clinically with IOH, based on history taking only. In six patients changes in cardiac output (CO) and systemic vascular resistance (SVR) were determined, and the underlying hemodynamics were analyzed.Results15/26 (58 %) patients with IOH had an abnormally large initial fall in systolic BP (≥40 mmHg). There was a large scatter in CO and SVR response after arising from supine [ΔCO at BP nadir median −8 % (range −37, +27 %); ΔSVR at BP nadir median −31 % (range −46, +10 %)]. The hemodynamic response after squatting showed a more consistent pattern, with a fall in SVR in all six patients [ΔCO at BP nadir median +23 % (range −12, +31 %); ΔSVR at BP nadir median −42 %, (range −52, −35 %)].InterpretationThe clinical diagnosis of IOH is based on history taking, as an abnormally large fall in systolic BP can only be documented in 58 %. For IOH upon standing after supine rest, the hemodynamic mechanism can be either a large fall in CO or in SVR. For IOH upon arising from squatting a large fall in SVR is a consistent finding.