Ingestion of the Non-Nutritive Sweetener Erythritol, but Not Glucose, Enhances Platelet Reactivity and Thrombosis Potential in Healthy Volunteers-Brief Report.

BACKGROUND: Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease-relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined. METHODS: Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released. RESULTS: Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930-7300] versus 3.75 [3.35-3.87] µmol/L; P<0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin (P<0.0001 for TRAP6 [thrombin activator peptide 6] and P=0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4; P<0.0001 for TRAP6 and P=0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4. CONCLUSIONS: Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04731363.

Altered central and peripheral haemodynamics during rhythmic handgrip exercise in young adults with SARS-CoV-2.

NEW FINDINGS: What is the central question of this study? Are central and peripheral haemodynamics during handgrip exercise different in young adults 3-4 weeks following infection with of SARS-CoV-2 compared with young healthy adults. What is the main finding and its importance? Exercising heart rate was higher while brachial artery blood flow and vascular conductance were lower in the SARS-CoV-2 compared with the control group. These findings provide evidence for peripheral impairments to exercise among adults with SARS-CoV-2, which may contribute to exercise limitations. ABSTRACT: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can have a profound impact on vascular function. While exercise intolerance may accompany a variety of symptoms associated with SARS-CoV-2 infection, the impact of SARS-CoV-2 on exercising blood flow (BF) remains unclear. Central (photoplethysmography) and peripheral (Doppler ultrasound) haemodynamics were determined at rest and during rhythmic handgrip (HG) exercise at 30% and 45% of maximal voluntary contraction (MVC) in young adults with mild symptoms 25 days after testing positive for SARS-CoV-2 (SARS-CoV-2: n = 8M/5F; age: 21 ± 2 years; height: 176 ± 11 cm; mass: 71 ± 11 kg) and were cross-sectionally compared with control subjects (Control: n = 8M/5F; age: 27 ± 6 years; height: 178 ± 8 cm; mass: 80 ± 25 kg). Systolic blood pressure, end systolic arterial pressure and rate pressure product were higher in the SARS-CoV-2 group during exercise at 45% MVC compared with controls. Brachial artery BF was lower in the SARS-CoV-2 group at both 30% MVC (Control: 384.8 ± 93.3 ml min-1 ; SARS-CoV-2: 307.8 ± 105.0 ml min-1 ; P = 0.041) and 45% MVC (Control: 507.4 ± 109.9 ml min-1 ; SARS-CoV-2: 386.3 ± 132.5 ml min-1 ; P = 0.002). Brachial artery vascular conductance was lower at both 30% MVC (Control: 3.93 ± 1.07 ml min-1  mmHg-1 ; SARS-CoV-2: 3.11 ± 0.98 ml min-1  mmHg-1 ; P = 0.022) and 45% MVC (Control: 4.74 ± 1.02 ml min-1  mmHg-1 ; SARS-CoV-2: 3.46 ± 1.10 ml min-1  mmHg-1 ; P < 0.001) in the SARS-CoV-2 group compared to control group. The shear-induced dilatation of the brachial artery increased similarly across exercise intensities in the two groups, suggesting the decrease in exercising BF may be due to microvascular impairments. Brachial artery BF is attenuated during HG exercise in young adults recently diagnosed with mild SARS-CoV-2, which may contribute to diminished exercise capacity among those recovering from SARS-CoV-2 like that seen in severe cases.

Carotid stiffness, intima-media thickness and aortic augmentation index among adults with SARS-CoV-2.

NEW FINDINGS: What is the central question of this study? We sought to investigate whether carotid stiffness, carotid intima-media thickness and the aortic augmentation index are altered in young adults 3-4 weeks after contraction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with young healthy adults. What is the main finding and its importance? We found that carotid stiffness, Young's modulus and the aortic augmentation index were greater in young adults who tested positive for SARS-CoV-2 compared with healthy young adults. These findings provide additional evidence for detrimental effects of SARS-CoV-2 on young adult vasculature, which might have implications for cardiovascular health. ABSTRACT: Contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed to cause decrements in vascular function of young adults. However, less is known about the impact of SARS-CoV-2 on arterial stiffness and structure, which might have additional implications for cardiovascular health. The purpose of this study was to assess the carotid artery stiffness and structure using ultrasound and the aortic augmentation index (AIx) using applanation tonometry in young adults after they tested positive for SARS-CoV-2. We hypothesized that carotid artery stiffness, carotid intima-media thickness (cIMT) and aortic AIx would be elevated in young adults with SARS-CoV-2 compared with healthy young adults. We evaluated 15 young adults (six male and nine female; 20 ± 1 years of age; body mass index, 24 ± 3 kg m-2 ) 3-4 weeks after a positive SARS-CoV-2 test result compared with young healthy adults (five male and 10 female; 23 ± 1 years of age; body mass index, 22 ± 2 kg m-2 ) who were evaluated before the coronavirus 2019 pandemic. Carotid stiffness, Young's modulus and cIMT were assessed using ultrasound, whereas aortic AIx and aortic AIx standardized to 75 beats min-1 (AIx@HR75) were assessed from carotid pulse wave analysis using SphygmoCor. Group differences were observed for carotid stiffness (control, 5 ± 1 m s-1 ; SARS-CoV-2, 6 ± 1 m s-1 ), Young's modulus (control, 396 ± 120 kPa; SARS-CoV-2, 576 ± 224 kPa), aortic AIx (control, 3 ± 13%; SARS-CoV-2, 13 ± 9%) and aortic AIx@HR75 (control, -3 ± 16%; SARS-CoV-2, 10 ± 7%; P < 0.05). However, cIMT was similar between groups (control, 0.42 ± 0.06 mm; SARS-CoV-2, 0.44 ± 0.08 mm; P > 0.05). This cross-sectional analysis revealed higher carotid artery stiffness and aortic stiffness among young adults with SARS-CoV-2. These results provide further evidence of cardiovascular impairments among young adults recovering from SARS-CoV-2 infection, which should be considered for cardiovascular complications associated with SARS-CoV-2.

COVID-19 is getting on our nerves: sympathetic neural activity and haemodynamics in young adults recovering from SARS-CoV-2.

KEY POINTS: The impact of SARS-CoV-2 infection on autonomic and cardiovascular function in otherwise healthy individuals is unknown. For the first time it is shown that young adults recovering from SARS-CoV-2 have elevated resting sympathetic activity, but similar heart rate and blood pressure, compared with control subjects. Survivors of SARS-CoV-2 also exhibit similar sympathetic nerve activity and haemodynamics, but decreased pain perception, during a cold pressor test compared with healthy controls. Further, these individuals display higher sympathetic nerve activity throughout an orthostatic challenge, as well as an exaggerated heart rate response to orthostasis. If similar autonomic dysregulation, like that found here in young individuals, is present in older adults following SARS-CoV-2 infection, there may be substantial adverse implications for cardiovascular health. ABSTRACT: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can elicit systemic adverse physiological effects. However, the impact of SARS-CoV-2 on autonomic and cardiovascular function in otherwise healthy individuals remains unclear. Young adults who tested positive for SARS-CoV-2 (COV+; n = 16, 8 F) visited the laboratory 35 ± 16 days following diagnosis. Muscle sympathetic nerve activity (MSNA), systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured in participants at rest and during a 2 min cold pressor test (CPT) and 5 min each at 30° and 60° head-up tilt (HUT). Data were compared with age-matched healthy controls (CON; n = 14, 9 F). COV+ participants (18.2 ± 6.6 bursts min-1 ) had higher resting MSNA burst frequency compared with CON (12.7 ± 3.4 bursts min-1 ) (P = 0.020), as well as higher MSNA burst incidence and total activity. Resting HR, SBP and DBP were not different. During CPT, there were no differences in MSNA, HR, SBP or DBP between groups. COV+ participants reported less pain during the CPT compared with CON (5.7 ± 1.8 vs. 7.2 ± 1.9 a.u., P = 0.036). MSNA was higher in COV+ compared with CON during HUT. There was a group-by-position interaction in MSNA burst incidence, as well as HR, in response to HUT. These results indicate resting sympathetic activity, but not HR or BP, may be elevated following SARS-CoV-2 infection. Further, cardiovascular and perceptual responses to physiological stress may be altered, including both exaggerated (orthostasis) and suppressed (pain perception) responses, compared with healthy young adults.

Vascular alterations among young adults with SARS-CoV-2.

While SARS-CoV-2 primarily affects the lungs, the virus may be inflicting detriments to the cardiovascular system, both directly through angiotensin-converting enzyme 2 receptor and initiating systemic inflammation. Persistent systemic inflammation may be provoking vascular dysfunction, an early indication of cardiovascular disease risk. To establish the potential effects of SARS-CoV-2 on the systemic vasculature in the arms and legs, we performed a cross-sectional analysis of young healthy adults (control: 5 M/15 F, 23.0 ± 1.3 y, 167 ± 9 cm, 63.0 ± 7.4 kg) and young adults who, 3-4 wk prior to testing, had tested positive for SARS-CoV-2 (SARS-CoV-2: 4 M/7 F, 20.2 ± 1.1 y, 172 ± 12 cm, 69.5 ± 12.4 kg) (means ± SD). Using Doppler ultrasound, brachial artery flow-mediated dilation (FMD) in the arm and single passive limb movement (sPLM) in the leg were assessed as markers of vascular function. Carotid-femoral pulse wave velocity (PWVcf) was asvsessed as a marker of arterial stiffness. FMD was lower in the SARS-CoV-2 group (2.71 ± 1.21%) compared with the control group (8.81 ± 2.96%) (P < 0.01) and when made relative to the shear stimulus (SARS-CoV-2: 0.04 ± 0.02 AU, control: 0.13 ± 0.06 AU, P < 0.01). The femoral artery blood flow response, as evidenced by the area under the curve, from the sPLM was lower in the SARS-CoV-2 group (-3 ± 91 mL) compared with the control group (118 ± 114 mL) (P < 0.01). PWVcf was higher in the SARS-CoV-2 group (5.83 ± 0.62 m/s) compared with the control group (5.17 ± 0.66 m/s) (P < 0.01). Significantly lower systemic vascular function and higher arterial stiffness are evident weeks after testing positive for SARS-CoV-2 among young adults compared with controls.NEW & NOTEWORTHY This study was the first to investigate the vascular implications of contracting SARS-CoV-2 among young, otherwise healthy adults. Using a cross-sectional design, this study assessed vascular function 3-4 wk after young adults tested positive for SARS-CoV-2. The main findings from this study were a strikingly lower vascular function and a higher arterial stiffness compared with healthy controls. Together, these results suggest rampant vascular effects seen weeks after contracting SARS-CoV-2 in young adults.

Frailty in the Advanced Heart Failure Patient: A Challenging, Neglected, Yet Potentially Modifiable Risk Factor.

Purpose of review: There is an increasing push for frailty assessment to become a routine part of the evaluation of potential candidates for advanced heart failure (AHF) therapies. The aim of this review is to highlight the importance of frailty in the care of the AHF patient. Recent findings: This review focuses on some of the available data for the assessment of frailty specifically in the AHF, durable mechanical circulatory support (MCS), and heart transplant (HT) patients, and explores some of the challenges in assessing frailty in these patient populations. Summary: As the presence of frailty can significantly impact outcomes after HT and durable MCS implantation, there should be an increased recognition of this entity during routine evaluation and management of the AHF patient.

Monthly transthoracic echocardiography in young adults for 6 months following SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can elicit acute and long-term effects on the myocardium among survivors, yet effects among otherwise healthy young adults remains unclear. Young adults with mild symptoms of SARS-CoV-2 (8M/8F, age: 21 ± 1 years, BMI: 23.5 ± 3.1 kg·m-2 ) underwent monthly transthoracic echocardiography (TTE) and testing of circulating cardiac troponin-I for months 1-6 (M1-M6) following a positive polymerase chain reaction test to better understand the acute effects and post-acute sequelae of SARS-CoV-2 on cardiac structure and function. Left heart structure and ejection fraction were unaltered from M1-M6 (p > 0.05). While most parameters of septal and lateral wall velocities, mitral and tricuspid valve, and pulmonary vein (PV) were unaltered from M1-M6 (p > 0.05), lateral wall s' wave velocity increased (M1: 0.113 ± 0.019 m·s-1 , M6: 0.135 ± 0.022 m·s-1 , p = 0.013); PV S wave velocity increased (M1: 0.596 ± 0.099 m·s-1 , M6: 0.824 ± 0.118 m·s-1 , p < 0.001); the difference between PV A wave and mitral valve (MV) A wave durations decreased (M1: 39.139 ± 43.715 ms, M6: 18.037 ± 7.227 ms, p = 0.002); the ratio of PV A duration to MV A duration increased (M1: 0.844 ± 0.205, M6: 1.013 ± 0.132, p = 0.013); and cardiac troponin-I levels decreased (M1: 0.38 ± 0.20 ng·ml-1 , M3: 0.28 ± 0.34 ng·ml-1 , M6: 0.29 ± 0.16 ng·ml-1 ; p = 0.002) over time. While young adults with mild symptoms of SARS-CoV-2 lacked changes to cardiac structure, the subclinical improvements to cardiac function and reduced inflammatory marker of cardiac troponin-I over 6 months following SARS-CoV-2 infection provide physiologic guidance to post-acute sequelae and recovery from SARS-CoV-2 and its variants using conventional TTE.

Plasma UCHL1, GFAP, Tau, and NfL Are Not Different in Young Healthy Persons With Mild COVID-19 Symptoms Early in the Pandemic: A Pilot Study.

Elevated levels of brain injury biomarkers have been found primarily in middle-aged or older persons experiencing moderate-to-severe COVID-19 symptoms. However, there is little research in young adults, and there is concern that COVID-19 causes brain injury even in the absence of moderate-to-severe symptoms. Therefore, the purpose of our study was to investigate whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, or ubiquitin carboxyl-terminal esterase L1 (UCHL1) are elevated in the plasma of young adults with mild COVID-19 symptoms. Twelve participants diagnosed with COVID-19 had plasma collected 1, 2, 3, and 4 months after diagnosis to determine whether NfL, GFAP, tau, and UCHL1 concentrations increased over time or whether plasma concentrations were elevated compared with COVID-19-naïve participants. We also compared plasma NfL, GFAP, tau, and UCHL1 concentrations between sexes. Our results showed no difference between NfL, GFAP, tau, and UCHL1 concentrations in COVID-19-naïve participants and COVID-19-positive participants at any of the four time points (p = 0.771). Within the COVID-19-positive participants, UCHL1 levels were higher at month 3 after diagnosis compared to month 1 or month 2 (p = 0.027). Between sexes, females were found to have higher UCHL1 (p = 0.003) and NfL (p = 0.037) plasma concentrations compared to males, whereas males had higher plasma tau concentrations than females (p = 0.024). Based on our data, it appears that mild COVID-19 in young adults does not increase plasma NfL, GFAP, tau, or UCHL1.

Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection.

Cross-sectional data indicate that acute SARS-CoV-2 infection increases resting muscle sympathetic nerve activity (MSNA) and alters hemodynamic responses to orthostasis in young adults. However, the longitudinal impact of contracting SARS-CoV-2 on autonomic function remains unclear. The aim of this study was to longitudinally track MSNA, sympathetic transduction to blood pressure (BP), and hemodynamics over 6 months following SARS-CoV-2 infection. Young adults positive with SARS-CoV-2 reported to the laboratory three times over 6 months (V1:41 ± 17, V2:108 ± 21, V3:173 ± 16 days post-infection). MSNA, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured at rest, during a cold pressor test (CPT), and at 30° head-up tilt (HUT). Basal SBP (p = 0.019) and DBP (p < 0.001) decreased throughout the 6 months, whereas basal MSNA and HR were not different. Basal sympathetic transduction to BP and estimates of baroreflex sensitivity did not change over time. SBP and DBP were lower during CPT (SBP: p = 0.016, DBP: p = 0.007) and HUT at V3 compared with V1 (SBP: p = 0.041, DBP: p = 0.017), with largely no changes in MSNA. There was a trend toward a visit-by-time interaction for burst incidence (p = 0.055) during HUT, wherein at baseline immediately prior to tilting, burst incidence was lower at V3 compared with V1 (p = 0.014), but there were no differences between visits in the 30 HUT position. These results support impairments to cardiovascular health, and potentially autonomic function, which may improve over time. However, the improvements in BP over 6 months recovery from mild SARS-CoV-2 infection are likely not a direct result of changes in sympathetic activity.

Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3-4 wk following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remain unknown. The purpose of this study was to elucidate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the 6 mo following infection. Assessments were performed at months 1, 2, 3, 4, and ∼6 following SARS-CoV-2 infection. Doppler ultrasound was used to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75 beats·min-1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. From months 1-6, a significant reduction in cfPWV was observed (month 1: 5.70 ± 0.73 m·s-1; month 6: 4.88 ± 0.65 m·s-1; P < 0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month 1: 123 ± 8 mmHg; month 6: 112 ± 11 mmHg) and mean arterial pressure (MAP; month 1: 97 ± 6 mmHg; month 6: 86 ± 7 mmHg) were observed (P < 0.05), although AIx@HR75 did not change over time. The month 1-6 change in cfPWV and MAP were correlated (r = 0.894; P < 0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month 1: 5,575 ± 2,242 pg·mL-1; month 3: 4,636 ± 1,621 pg·mL-1; P < 0.05) without a change in ICAM-1. A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks.NEW & NOTEWORTHY We sought to investigate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults for 6 mo following infection. Carotid femoral pulse wave velocity was significantly reduced while carotid stiffness measures remained unaltered over the 6-mo period. These findings suggest several months of recovery from infection may be necessary for young adults to improve various markers of arterial stiffness, possibly contributing to cardiovascular health and recovery among those infected with SARS-CoV-2.

Tracking peripheral vascular function for six months in young adults following SARS-CoV-2 infection.

SARS-CoV-2 infection is known to instigate a range of physiologic perturbations, including vascular dysfunction. However, little work has concluded how long these effects may last, especially among young adults with mild symptoms. To determine potential recovery from acute vascular dysfunction in young adults (8 M/8F, 21 ± 1 yr, 23.5 ± 3.1 kg⋅m-2 ), we longitudinally tracked brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH) in the arm and hyperemic response to passive limb movement (PLM) in the leg, with Doppler ultrasound, as well as circulating biomarkers of inflammation (interleukin-6, C-reactive protein), oxidative stress (thiobarbituric acid reactive substances, protein carbonyl), antioxidant capacity (superoxide dismutase), and nitric oxide bioavailability (nitrite) monthly for a 6-month period post-SARS-CoV-2 infection. FMD, as a marker of macrovascular function, improved from month 1 (3.06 ± 1.39%) to month 6 (6.60 ± 2.07%; p < 0.001). FMD/Shear improved from month one (0.10 ± 0.06 AU) to month six (0.18 ± 0.70 AU; p = 0.002). RH in the arm and PLM in the leg, as markers of microvascular function, did not change during the 6 months (p > 0.05). Circulating markers of inflammation, oxidative stress, antioxidant capacity, and nitric oxide bioavailability did not change during the 6 months (p > 0.05). Together, these results suggest some improvements in macrovascular, but not microvascular function, over 6 months following SARS-CoV-2 infection. The data also suggest persistent ramifications for cardiovascular health among those recovering from mild illness and among young, otherwise healthy adults with SARS-CoV-2.