Impaired Cardiovascular Function Research Articles

Effect of Different Rates of Rambutan Peel Extract on Visfatin and Cardiac Troponin I Response in Type 2 Diabetic Rats Induced with Streptozotocin

Background: The aim of this study was to investigate the effects of STZ (Streptozotocin) and Rambutan peel extract (RPE) on serum visfatin and cardiac response in experimental Type 2 diabetic rats. Methods: In this study, 64 adult male Wistar albino rats, aged between 8-10 weeks, were used. 8 groups were randomly selected, each containing 8 rats as Control (C), R100 (RPE 100 mg/kg group given with oral gavage route of administration (OGRA), R200 (RPE 200 mg/kg group given with OGRA), R300 (RPE 300 mg/kg group given with OGRA); Diabetes Control (DC): STZ 50 mg/kg i.p administered group, DR100 (D+100 mg/kg JPE), DR200 (D+200 mg/kg JPE), DR300 (D+300 mg/kg JPE). The study lasted a total of 31 days, including adaptation (7 days), induction of diabetes (3 days), and trial period (21 days). Blood samples were taken from the tail vein (vena caudalis) of all subjects on days 0 and 21 of the study. Visfatin and cTnI levels in the serum samples were measured and evaluated by ELISA method. Result: While the increase in mean serum visfatin and cTnI levels in diabetic groups was seen mostly in DC groups, the most significant decrease in mean serum visfatin level due to the addition of RPE was determined in DR100 groups (p less than 0.01).As a result, it was concluded that the administration of 100 mg/kg RPE in rats had no adverse effects. It was concluded that RPE, which has a cardioprotective effect by regulating the visfatin response that plays a role in the development of diabetes, may be useful in supporting the impaired cardiovascular system function that occurs in diabetes.

Effects of Cross-Sex Hormone Therapy on Metabolic Parameters and Aortic Relaxation in Castrated Male Rats

With the rising awareness, the number of individuals identifying themselves as transgender in the US is increasing over the years. Cross-sex hormone therapy (CSHT) may alter numerous cardiometabolic parameters leading to the increased risk of cardiovascular diseases (CVD) in transgender population. Epidemiological studies suggest that transgender females (male to female, MtF) on estrogen therapy develop higher risk of CVD compared to transgender males (female to male, FtM) taking testosterone. Underlying mechanisms of impaired cardiovascular functions in MtF are not well documented. This study was undertaken to examine the effects of 17β-estradiol (E2) on certain cardiometabolic parameters and aortic reactivity in castrated (CAS) male Sprague Dawley (SD) rats. The 8-10-weeks old CAS rats were subcutaneously implanted with either 1.5 mg of E2 (CAS+E2) or placebo (CAS+PL) containing pellets for ~35 days. The age-matched SD intact male (IM) rats were also included in the experimental groups. After performing the glucose tolerance test, animals were sacrificed, and the blood was collected for later measurements of the HbA1C and triglyceride (TG) levels. Endothelium-dependent vasorelaxation (EDV) to acetylcholine (ACh) in aortic rings pre-contracted with phenylephrine (PE) was measured before and after treatment with indomethacin (a cyclooxygenase inhibitor), followed by L-NAME [a nonselective nitric oxide (NO) synthase (NOS) inhibitor]. Contractile responses to PE before and after L-NAME in aortic rings and sodium nitroprusside (SNP)-induced relaxation responses in endothelium-denuded rings were also measured. Here, we report the decreased body weight and visceral white adipose tissue, and improved HbA1C and glucose tolerance in E2-treated CAS rats. However, the E2-treated CAS rats exhibited elevated plasma level of TG. Furthermore, the vascular relaxation to ACh was significantly impaired in aortas from this group compared to those in CAS+PL and IM rats. The impairment of ACh responses in CAS+E2 rats was accompanied by a significant decrease in NO contribution to ACh vasorelaxation. The basal NO levels and the smooth muscle sensitivity to NO were not altered, whereas the maximum contractile responses to PE were enhanced in aortas of CAS+E2 group compared to IM. In conclusion, our data suggests that the glucose homeostasis was improved in CAS+E2 rats. Regardless, this group exhibited increased level of TG in plasma and decreased aortic vasorelaxation to ACh. The impairment of EDV in E2-treated CAS rats might be due to reduced NO-mediated vasorelaxation or increased contractile responses observed in this group. Additional studies are needed to document the underlying mechanisms for improvement of glucose homeostasis and impairment of EDV in CAS+E2 rats. NIDA/NIGMS, 1SC1DA052120-01 to MF and Bridge Grant from University of the Pacific to RR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A new perspective on cardiovascular function and dysfunction during endurance exercise: identifying the primary cause of cardiovascular risk.

Exercise mechanical efficiency typically falls within the range of approximately 20 to 25%. This means that a great part of the metabolic energy converted to generate movement is released as heat. Therefore, the rise in core temperature during endurance exercise in humans is proportional to generated work. Cutaneous vasodilation occurs when the core temperature threshold is reached. The rise in heart rate in response to thermal stress is a cardiovascular response that increases cardiac output and skin blood flow. The cardiovascular response during endurance exercise is a complex phenomenon potentially influenced by the involvement of nitric oxide in active thermoregulatory vasodilation. Excessive exercise can create high oxidative stress by disrupting the balance between free radicals' production and scavenging, resulting in impaired cardiovascular function. The above considerations are related to the severity and duration of endurance exercise. The first focus of this narrative review is to provide an updated understanding of cardiovascular function during endurance exercise. We aim to explore the potential role of oxidative stress in causing cardiovascular dysfunction during endurance exercise from a fresh perspective. Additionally, we aim to identify the primary factors contributing to cardiovascular risk during strenuous prolonged exercise by highlighting recent progress in this area, which may shed light on previously unexplained physiological responses. To ascertain the effect of endurance exercise on cardiovascular function and dysfunction, a narrative review of the literature was undertaken using PubMed, ScienceDirect, Medline, Google Scholar, and Scopus. The review highlighted that high oxidative stress (due to high levels of catecholamines, shear stress, immune system activation, and renal dysfunction) leads to a rise in platelet aggregation during endurance exercise. Importantly, we clearly revealed for the first time that endothelial damage, vasoconstriction, and blood coagulation (inducing thrombosis) are potentially the primary factors of cardiovascular dysfunction and myocardial infarction during and/or following endurance exercise.

Post-coronavirus disease-19: the impact of cardiopulmonary rehabilitation on arterial stiffness, left ventricular deformation, and ventricular-arterial coupling

Abstract Introduction Although coronavirus disease-19 (COVID-19) is a primarily a respiratory disease, impairment of cardiovascular function has been documented, even in the post-acute phase. Cardiopulmonary rehabilitation could represent an appealing approach in the management of cardiovascular sequelae of post-COVID-19, which may affect arterial and left ventricular function, ultimately influencing ventricular-arterial coupling (VAC). Purpose In this study, we assess the impact of a post-acute COVID-19 rehabilitation program on arterial stiffness, left ventricular deformation, and VAC. Methods We enrolled 60 convalescent patients from COVID-19 and one-month post-acute disease were randomized at 1:1 ratio in a 3-month cardiopulmonary rehabilitation program (study group) or not (control group). The levels of pro-inflammatory interleukin-1β (IL-1β) were determined. Arterial stiffness was evaluated by carotid-femoral Pulse wave velocity (cf-PWV) at 1 month and at 4 months post-acute disease. Transthoracic echocardiography was performed, and left ventricular global longitudinal strain (LV-GLS) was estimated. Finally, the ratio of cf-PWV/LV-GLS was calculated as an index of VAC. Results There were no significant differences in major risk factors across the studied groups (age, sex, body mass index, smoking, hypertension, diabetes mellitus, dyslipidemia). Moreover, patients across the study groups did not differ regarding the levels of IL-1β. Although cf-PWV was similar in the study and the control group at baseline, it was improved only in the study group (8.2±1.3m/sec vs. 6.6±1.0m/sec, p<0.001) but not in the control group (8.9±1.8m/sec vs. 8.8±1.9m/sec, p=0.74). Similarly, for GLS, no differences were noted at baseline. However, the study group exhibited a significant improvement during the study (-19.6±2.0% vs. -21.3±1.9%, p<0.001), while no changes were observed in the control group (-18.7±2.9% vs. -18.3±2.1%, p=0.15). Finally, VAC was significantly ameliorated only in patients receiving cardiopulmonary rehabilitation (-0.43±0.11m/s% vs. -0.31±0.06m/s%, p<0.001). When individuals undergoing cardiopulmonary rehabilitation were stratified according to median baseline IL-1β levels, those presenting with lower concentrations experienced a significant benefit in ΔVAC (IL-1β<8.4pg/ml: 0.14±0.08m/s% vs. IL-1β≥8.4pg/ml: 0.09±0.05m/s%, p=0.04). Conclusion A 3-month cardiopulmonary rehabilitation program following the acute phase of COVID-19 accelerates the recovering of arterial and ventricular function, especially in individuals with a lower baseline inflammatory burden.

Vascular senescence controls the neuro-cardiac interface in the aging heart

Abstract Aging is a major risk factor for impaired cardiovascular function. The aging heart is characterized by vascular dysfunction, increased hypertrophy, fibrosis and electrophysiological alterations. Studies show impaired endothelial cell (EC) function associates with senescence in aging. Since vessels and nerves align, and this interplay is critical for tissue homeostasis, we studied whether an impairment of the neuro-vascular interface may contribute to age-associated pathologies in the heart. To study the innervation of the aging mouse heart, we histologically assessed the cardiac autonomic nervous system in 3- and 20-month old mice using the pan-neuronal marker Tuj1 and the sympathetic marker TH. Interestingly, sympathetic innervation of the left ventricle, especially around arteries, was reduced by 0.66±0.07-fold with aging (p<0.05) indicating that aging reduces innervation of the left ventricle. Similar findings were observed in premature aging models of TERT-KO and EC-transgenic progeria mice. Electrophysiological studies confirmed an increased incidence of ventricular arrhythmias and reduced heart rate variability in aged mice. To determine the potential contribution of neurovascular cells, we analyzed gene expression of isolated ECs in aging mouse hearts by bulk RNA sequencing. Aging significantly induced the expression of genes associated with GO-terms related to neuronal cell death and axon injury. Sema3a, an axon repelling factor, was significantly increased in ECs of aged mice hearts, which was confirmed by qPCR and by histology (p<0.05). Next we determined the mechanism of Sema3a regulation. We show that miR-145 acts as an up-stream regulator of Sema3a expression. miR-145-/- mice showed increased Sema3a expression and reduced cardiac innervation. We observed an increase in acidic β-gal activity as a marker for cellular senescence in the aging heart, particularly in the proximate arterial space. In addition, Sema3a expression was significantly increased in senescent ECs in vitro, thus suggesting a putative role for senescence to impair cardiac innervation. To test whether eliminating senescent cells may restore left ventricular axon density, we treated 18-month old mice with a combination of the two senolytic drugs dasatinib and quercetin, which are known to deplete senescent cells in vivo. After 2 months of treatment, cellular senescence was reduced by 0.4±0.1-fold (p<0.05) in aged hearts. Endothelial expression of Sema3a was also reduced. Importantly, senolytic treatment restored ventricular innervation, augmented heart rate variability, and normalized electrophysiological abnormalities (all p<0.05). In conclusion, we show that aging augments axon repelling signals in ECs and reduces left ventricular innervation. The depletion of senescent cells prevented age-induced impairment of innervation and normalized electrophysiological abnormalities suggesting a critical role of senescence-associated axon repulsion in the aging heart.

Abstract 12226: Aging Impairs the Neuro-Vascular Interface in the Heart

Aging is a major risk factor for impaired cardiovascular function. The aging heart is characterized by vascular dysfunction, increased hypertrophy, fibrosis and electrophysiological alterations. However, the interaction between the different age-associated changes in cardiac remodelling is poorly define. Since vessels are aligned with nerves, and this interplay is critical for tissue homeostasis, we investigated whether an impairment of the neuro-vascular interface may contribute to age-associated pathologies in the heart. We show that aging reduces sympathetic and sensory nerve fibers, which both align to arteries and arterioles. Aging induced a dysregulation of vascular-derived neuro-regulatory genes, especially the axon repellent factor Sema3A, which was augmented by 2.4±0.1-fold in old heart endothelial cells. Consistently, endothelial Sema3a overexpression reduced axon density in vivo, thus mimicking the observed aged heart phenotype. Since cellular senescence was induced at the same time point when nerve density declined (16 months of age) and senescence endothelial cells showed a higher expression of Sema3a, we hypothesized that endothelial senescence may contribute to cardiac denervation. Indeed, supernatants of senescent endothelial cells reduced neurite outgrowth in vitro in a Sema3A-dependent manner. In vivo studies further confirmed that endothelial-specific induction of senescence by overexpression of Progerin induced left ventricular denervation and induced Sema3a expression. By contrast, the pharmacological removal of senescent cells by the senolytic drugs dasatinib and quercetin rescued age-induced denervation and prevented the age-induced induction of endothelial Sema3a expression. Functional studies additionally demonstrated that endothelial senescence reduced heart rate variability, while senolytics preserved heart rate variability, restored age-associated declines in sympathetic and parasympathetic activity and reduced age-associated increase in arrhythmias. These data suggest that senescence-associated regulation of neuro-regulatory genes in endothelial cells is associated with reduced nerve density and, thereby, contributes to age-associated cardiac dysfunction.

Clinical characteristics and prognosis of patients with isolated cardiac sarcoidosis: Insights from the ILLUMINATE-CS study.

Data on the clinical features and prognosis of patients with isolated cardiac sarcoidosis (iCS) are limited. This study evaluated the clinical characteristics and prognostic impact of iCS. This was a secondary analysis of the ILLUMINATE-CS study, a multicentre, retrospective registry investigating the clinical characteristics and prognosis of cardiac sarcoidosis. iCS was diagnosed according to the 2016 Japanese Circulation Society (JCS) guidelines. Clinical characteristics and prognosis were compared between patients with iCS and systemic cardiac sarcoidosis (sCS). The primary outcome was a combined endpoint of all-cause death, hospitalization for heart failure, or fatal ventricular arrhythmia events. Among 475 patients with CS (mean age, 62.0 ± 10.9 years; female ratio, 59%) diagnosed by the JCS guidelines, 119 (25.1%) were diagnosed with iCS. Patients with iCS had a higher prevalence of a history of atrial fibrillation or hospitalization for heart failure, or lower left ventricular ejection fraction than those with sCS. During a median follow-up of 42.3 (interquartile range, 22.8-72.5) months, 141 primary outcomes (29.7%) occurred. Cox proportional hazard analysis revealed that iCS was a significant risk factor for the primary outcome in the unadjusted model (hazard ratio [HR] 1.62; 95% confidence interval [CI] 1.12-2.34; p = 0.011). However, this association was not retained after adjustment for other covariates (adjusted HR 1.27; 95% CI 0.86-1.88; p = 0.226). Patients with iCS had more impaired cardiovascular function at the time of diagnosis than those with sCS. However, iCS was not independently associated with poor prognosis after adjustment for prognostic factors.

Hepatorenal and renocardial syndrome in young patients with acute glomerulonephritis

In this paper we discuss classical types of acute glomerulonephritis in young adults, when the intake of paracetamol and diclofenac led to a dysfunctional and organic liver injury, at the same time it negatively affected the course of acute glomerulonephritis. To study the characteristics of the development of acute reno-cardial syndrome (ARCS) Goal: Assessment of cause and effect relations of renal, hearts and liver injuries in young adults in acute post-streptococcal glomerulonephritis (APSG). With acute nephritic syndrome (ANS) complicated by acute kidney injury (AKI) and without it, to identify the role of the etiological factor on the course of APSG. Methods and Material: 220 male patients with APSG with ANS aged 18-20 were examined. The patients were divided into 2 groups based on the functional state of kidneys. The first group included 140 patients with APSG without ANS, the second group included 80 patients with AKI. Results: Out 66 patients had subclinical liver injury, which resulted from the effect of antipyretic hepatotoxic drugs taken in the initial stage of the disease. Due to the toxic and immunological liver injury, levels of transaminases increase, and albumin levels decrease. These changes occur along with the development of APSG and are correlated with some laboratory values. Impairment of cardiovascular function was observed in all 220 patients. ECG and Echocardiography studies conducted during the cardiac asthma attacks occurred as a decrease of voltage, broadening of the P wave, lengthening of the PQ interval, broadening of the QRS complex, dilatations of the right and left atrium. The severity of clinical manifestations of AKI and ARCS correlates with the degree of macrohematuria, GFR decrease, complement C3 fraction, monocyte. Conclusion. In APSG liver injury has a toxicoallergic character. Frequency of liver injury depends on specific features of a particular organism, it does not depend on the dose of the taken drug. In case of any type of acute glomerulonephritis it is necessary to assess the functional state of liver and after the treatment of the main disease hepatologist follow-up of patients is recommended. Thus in the development of acute reno-cardial syndrome (ARCS) the degree of manifestation of hypervolemia with hypertension, as a result of active immune inflammation of the glomerular apparatus with the development of AKI, plays the main role in the development of ARCS with APSG.. As a rule ARCS in case of APSG with ANS in young adults has a successful outcome.

Acute exposure to chlorpyrifos differentially impacts survival and cardiovascular function of normotensive and hypertensive rats

Hypertension is the most important and well-known risk factor for cardiovascular disease (CVD). Recently, acute organophosphate (OP) poisoning has also been pointed as a CVD risk factor. Despite these evidence, no studies have contrasted the cardiovascular (CV) effects of OP poisoning under conditions of normotension and hypertension. We hypothesized that hypertensive rats would have a greater impairment of CV function after acute exposure to chlorpyrifos (CPF), an OP compound. 12-14 week-old male normotensive Wistar and Spontaneously Hypertensive rats (SHRs) were intraperitoneally (i.p.) injected with saline (NaCl 0.9%) or 20 mg.kg-1 of CPF, a previously shown sublethal dose in normotensive rats. 24-hour survival was recorded and through cannulation of the femoral artery and vein, we assessed blood pressure (BP) and heart rate (HR) recordings and chemically activated the Bezold-Jarisch Reflex (BJR), the Chemoreflex (CR), as well as assessed the cardiac autonomic tone (AUT). BJR was activated by phenylbiguanide (PBG; 1.5; 3; 6; 12; 24 μg/kg; i.v.) and the CR by potassium cyanide (KCN, 10, 20, 40 and 80 μg/ rat; i.v.) injections, while the AUT was assessed by pharmacological blockade with atenolol (4mg.kg-1, i.v) and atropine (2mg.kg-1, i.v). CPF acute exposure induced 33% mortality in SHR without leading to lethality in Wistar rats. CPF poisoning impaired the BJR hypotensive response in Wistar rats for all PBG doses tested (ΔDBP: - 33.83±4.88 vs. -14.16±2.68; -44.58±3.48 vs. -30.58±2.16; -66.16±2.50 vs. -36.16±2.54; -72.66±2.66 vs. -47.91±2.50; -78.66±2.35 vs.-61.58±2.40; p<0.05 Wistar saline vs Wistar CPF) and the bradycardic response at the dose of 6 and 12μg/kg, respectively (ΔHR: -268.66±14.77 vs. -216.66±11.11; -304.58±13.42 vs. -241.66±11.01; p<0.05 Wistar saline vs Wistar CPF), without affecting the SHR strain. No CPF-induced changes were observed for the CR and AUT between strains. Our findings show that, despite being sublethal in normotensive rats, CPF lead to mortality in hypertensive rats. However, contrary to our hypothesis, CPF poisoning did not further impaired CV function in SHR, but significantly worsen BJR function in Wistar rats. Despite not producing greater impairment in CV function, CPF poisoning leads to greater mortality under hypertension, which may impose a significant risk in individuals with this comorbidity. Aitken AV, was recipeint of Fapes Foundation scholarship. Minassa VS, Batista TJ were recipients of Capes Foundation scholarship. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight

BackgroundIndividuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented.ResultsGenomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults.ConclusionsThese findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Cardiac Manifestations of COVID-19 and COVID-19 Vaccine

Covid-19 pandemic is an unprecedented health issue across the globe. Covid-19 is known to affect multiple organ system of the body including cardiovascular system. The incidence of acute cardiac injury in COVID-19 patients has been estimated to be approximately 8–12%. COVID-19 is often found to be complicated with hypercoagulable state resulting in to thrombotic events. Covid-19 vaccines has also been found associated with deterioration of cardiovascular function among patients having risk factors and even in healthy young adults. Improved survival has been demonstrated by the timely implementation of suitable reperfusion and supportive therapy. A large, reliable multicenter data is needed to establish a relation between Covid-19 vaccine and adverse cardiovascular outcome.

Analysis Of Changes In Endothelin-1 (Et-1) And F2-Isoprostane Levels After The 30 Km Event In The Makassar Bike Community At The "Bike For Health" Event

This study aims to determine changes in ET-1 and F2-isoprostane levels after a 30 km cycling event in the Makassar cycling community. This study used a pre-experimental with one group pretest-posttest design on 30 male cyclists aged 30-60 years. The sampling technique used is the purposive sampling method. The pretest was carried out the day before the 30 km cycling event, then the post-test was carried out 2 hours after the cycling event. Blood testing is done with an ELISA Kit. Data were analyzed using the Wilcoxon test to see changes in ET-1 and F2-isoprostane levels after cycling events. The correlation of changes in ET-1 and F2-isoprostane levels was analyzed using the Spearman test. The results of this study found that the 30 km cycling event had no significant effect on changes in levels of ET-1 (p=0.082) and F2-isoprostane, which means that it has no potential to increase the body's oxidative stress (p=0.688). Changes in ET-1 levels did not correlate with changes in F2-isoprostane levels which showed no association with impaired cardiovascular function (p=0.102).

Blood pressure responses are dependent on call type and related to hypertension status in firefighters

Background Impaired cardiovascular health is a concern for firefighters, with over 50% of line-of-duty deaths having cardiac causes. Many firefighters have hypertension and <25% have their blood pressure (BP) controlled. The alarm response could be an unidentified cardiac risk, but interestingly, the BP response to different calls and on-the-job activity is unknown. Purpose We aimed to measure the physiological stress resulting from different call types (fire, medical) and job activity (riding apparatus, pre-alert alarms) through ambulatory BP (ABP) monitoring in a population of firefighters. Materials and methods During 111 12-h work shifts firefighters wore an ABP monitor. BP was measured at 30-min intervals and manual measurements were prompted when the pager went off or whenever they felt stress. Results Firefighters were hypertensive (124.3 ± 9.9/78.1 ± 6.7 mmHg), overweight (30.2 ± 4.6 kg/m2), middle-aged (40.5 ± 12.6 years) and experienced (17.3 ± 11.7 years). We calculated an average 11% increase in systolic and 10.5% increase in diastolic BP with alarm. Systolic BP (141.9 ± 13.2 mmHg) and diastolic BP (84.9 ± 11.1 mmHg) and the BP surges were higher while firefighters were responding to medical calls compared to fire calls. Between BP groups we found that medical call systolic BP (p = .001, d = 1.2), diastolic BP (p = .017, d = 0.87), and fire call systolic BP (p = .03, d = 0.51) levels were higher in the hypertensive firefighters. Conclusion This is the first report of BP surge responses to alarms and to occupational activities in firefighters, and medical calls elicited the largest overall responses.

Afterload-related cardiac performance is a powerful hemodynamic predictor of mortality in patients with chronic heart failure.

Afterload-related cardiac performance (ACP), a diagnostic parameter for septic cardiomyopathy, integrates both cardiac performance and vascular effects and could predict prognosis in septic shock. We hypothesized that ACP would also correlate with clinical outcomes in patients with chronic heart failure (HF). A retrospective study. We retrospectively studied consecutive patients with chronic HF who underwent right heart catheterization and established an expected cardiac output-systemic vascular resistance (CO-SVR) curve model in chronic HF for the first time. ACP was calculated as COmeasured/COpredicted × 100%. ACP > 80%, 60% < ACP ⩽ 80%, and ACP ⩽ 60% represented less impaired, mildly impaired, and severely impaired cardiovascular function, respectively. The primary outcome was all-cause mortality, and the secondary outcome was event-free survival. A total of 965 individual measurements from 290 eligible patients were used to establish the expected CO-SVR curve model (COpredicted = 53.468 × SVR -0.799). Patients with ACP ⩽ 60% had higher serum NT-proBNP levels (P < 0.001), lower left ventricular ejection fraction (P = 0.001), and required dopamine more frequently (P < 0.001). Complete follow-up data were available in 263 of 290 patients (90.7%). After multivariate adjustment, ACP remained associated with both primary outcome (hazard ratio (HR) 0.956, 95% confidence interval (CI) 0.927-0.987) and secondary outcome (HR 0.977, 95% CI 0.963-0.992). Patients with ACP ⩽ 60% had the worst prognosis (all P < 0.001). ACP was significantly more discriminating (area under the curve of 0.770) than other conventional hemodynamic parameters in predicting mortality (Delong test, all P < 0.05). ACP is a powerful independent hemodynamic predictor of mortality in patients with chronic HF. ACP and the novel CO-SVR two-dimensional graph could be useful in assessing cardiovascular function and making clinical decisions. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02664818.

Red cell infusion but not saline is effective for volume expansion in preterm piglets.

A common first-line treatment for supporting cardiovascular function in preterm infants is volume expansion using saline, but this does not improve outcomes. This study aimed to determine if volume expansion with saline increases blood volume, blood pressure and cerebral oxygenation; and if volume expansion with packed red blood cells (RBC) is more effective. We hypothesized that RBC infusion is more effective than saline for increasing blood volume and maintaining cardiovascular function and cerebral oxygenation. Five groups of preterm piglets (98/115d gestation) were infused with saline (10 or 20 mL/kg) or RBC (10 or 20 mL/kg) or no treatment. Blood volume, blood pressure, central venous pressure, heart rate, carotid flow, cerebral oxygenation, arterial pH, base excess, and lactate levels were assessed for 6 h after treatment started. Both RBC groups had significant increases in blood volume, and improved measures of cardiovascular function, cerebral oxygenation and metabolic acidosis. Saline infusion did not increase blood volume or measures of cardiovascular function, cerebral oxygenation or metabolic acidosis. The results suggest that the deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in premature babies, may be reversed or halted by more effective support of blood volume. Blood volume decreases after birth in preterm piglets and this decrease is associated with deteriorating cardiovascular function and cerebral oxygenation. Infusion of saline does not increase blood volume nor prevent deterioration in cardiovascular function. Infusion of packed red blood cells results in an increase in blood volume and improvements in cardiovascular function and cerebral oxygenation. Deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in human preterm neonates, may be reversed or halted by more effective support of blood volume.

Magnetismm-4: An Open Label, Phase 1B/2 Umbrella Study of Elranatamab in Combination with Other Anti-Cancer Treatments for Patients with Multiple Myeloma

Background Elranatamab (PF-06863135) is a humanized bispecific molecule that targets multiple myeloma (MM) cells via B-cell maturation antigen (BCMA) and T cells via CD3 to induce T cell-mediated cytotoxicity. In MagnetisMM-1 (NCT03269136), an ongoing, phase 1 study in patients with relapsed or refractory MM (RRMM), subcutaneous (SC) elranatamab yielded an overall response rate (ORR) of 64% and had a manageable safety profile (Jakubowiak et al, J Clin Oncol, 2022). In the phase 2 MagnetisMM-3 (NCT04649359) study in patients with heavily pretreated RRMM, SC elranatamab was well tolerated and yielded an ORR of 61% at the recommended phase 2 dose (Lesokhin et al, J Clin Oncol, 2022). Study Design and Methods MagnetisMM-4 (NCT05090566) is a phase 1B/2, open label, non-randomized, multicenter, umbrella study of elranatamab in combination with other anti-cancer treatments for patients with MM. The estimated enrollment is 105 patients. The study is split into 2 sub-studies (Figure 1). In each sub study, a 2 step-up priming dose of elranatamab will be employed to mitigate the risk of cytokine release syndrome and a Bayesian logistic regression model will be utilized for dose escalation. Sub-study A (SSA) is comprised of 2 phases in which patients will receive elranatamab + the gamma-secretase inhibitor (GSI) nirogacestat. Studies have shown that GSIs block BCMA cleavage and can potentially enhance BCMA-directed therapy (Eastman et al, Blood, 2019; Pont et al, Blood, 2019; Cowan et al, Blood, 2019). Phase 1 of SSA is designed to evaluate the safety, tolerability and select a recommended dose and regimen for the combination of elranatamab and nirogacestat. The primary endpoint for SSA Phase 1 is dose limiting toxicity (DLT) up to 35 days. Phase 2 of SSA will further evaluate the efficacy and safety of the combination of elranatamab and nirogacestat. The primary endpoint for SSA phase 2 is objective response rate (ORR) assessed every 4 weeks for ~2 years. A key secondary endpoint in both phases of SSA is the incidence of treatment-emergent adverse events (TEAEs). In sub-study B (SSB), patients will receive elranatamab + lenalidomide + dexamethasone. The dose escalation part of SSB is designed to assess the safety and tolerability of elranatamab in combination with lenalidomide and dexamethasone. The primary outcome of the dose escalation part is DLT up to 42 days. The dose expansion part of SSB is designed to evaluate the overall safety profile of elranatamab in combination with lenalidomide and dexamethasone. The primary endpoints of the dose expansion part of SSB are incidence of TEAEs and laboratory abnormalities across the duration of the study. A key secondary endpoint in SSB is ORR. Additional secondary endpoints in both SSA and SSB are time to response, duration of response, complete response (CR) rate, duration of CR, progression-free survival, overall survival, minimal residual disease negativity rate, immunogenicity to elranatamab, and elranatamab pharmacokinetics. Inclusion criteria in SSA and SSB include age ≥18 years, RRMM with ≥3 prior lines of therapy, refractory to at least one immunomodulatory drug, one proteasome inhibitor, and one anti-CD38 antibody, measurable disease by serum M-protein ≥0.5g/dL, urinary M-protein excretion ≥200mg/24h, or serum immunoglobulin free light chain (FLC) ≥10mg/dL and abnormal serum immunoglobulin kappa to lambda FLC ratio, and Eastern Cooperative Oncology Group performance status ≤1 (Table 1). Exclusion criteria include active plasma cell leukemia, amyloidosis, stem cell transplant within 12 weeks prior to enrolment or active graft-versus-host disease, POEMS syndrome, any active uncontrolled infection, impaired cardiovascular function or clinically significant cardiovascular disease within 6 months prior to enrolment, and previous administration with an investigational drug within 30 days or 5 half-lives preceding the first dose of study treatment. In SSA, patients who received prior treatment with a BCMA-bispecific antibody are excluded, and in SSB, patients who received prior treatment with BCMA-directed therapy are excluded. The study is enrolling the Phase 1 portions and is being opened at multiple sites in the United States and Canada. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Skin Biopsy and Quantitative Sudomotor Axon Reflex Testing in Patients With Postural Orthostatic Tachycardia Syndrome.

No formal diagnostic criteria exist for the neuropathic subtype of postural orthostatic tachycardia syndrome (POTS). Skin biopsy and quantitative sudomotor axon reflex testing (QSORT) are preferred methods of assessment for autonomic small fiber neuropathy (SFN). This study characterizes the utility of these testing methods at a tertiary center and identifies clinical features associated with abnormal testing. Medical records of 2658 patients undergoing tilt table testing at a single institution between June 2018 and December 2020 were reviewed. Patients with postural orthostatic tachycardia syndrome were included for analysis of intraepidermal nerve fiber density (IENFD), sweat output, comorbidities, symptoms, measures of cardiovascular autonomic function, and serum antibody levels. 356 patients (90% female, mean age 31 ± 10) met the diagnostic criteria for postural orthostatic tachycardia syndrome. Of 211 patients who underwent quantitative sudomotor axon reflex testing, 70 (33%) demonstrated reduced sweat output. These patients were more likely to demonstrate sympathetic impairment during the Valsalva maneuver. Of 80 patients who underwent skin biopsies, 19 (24%) demonstrated reduced intraepidermal nerve fiber density. These patients tended to be older and have reduced heart rate variability during deep breathing. Neither test was associated with specific serum antibodies, symptoms, or comorbidities, though there was a trend toward higher rates of comorbid autoimmune disease in patients with abnormal testing. A subset of patients with postural orthostatic tachycardia syndrome have evidence of small fiber neuropathy. These patients tend to have impaired cardiovascular autonomic function but are otherwise similar to patients with no evidence of small fiber neuropathy.

Cardiovascular autonomic nervous function in 7–12 years old children conceived naturally or by ART with frozen and fresh embryo transfer

Abstract Background Cardiovascular autonomic nervous functions (CANF) exert important homeostatic mechanisms to prevent major arterial blood pressure fluctuations by adjusting heart rate (HR), cardiac contractility, and peripheral vascular tone. Children conceived by assisted reproductive technologies (ART) are at risk of increased carotid intima-media thickness, insulin resistance, arterial stiffness, and hypertension. CANF is impaired in children with obesity and diabetes mellitus, and conductance artery stiffness is documented to influence CANF. CANF may therefore be hypothetized to be impaired in children conceived by ART. Purpose This is the first study to investigate whether children conceived by ART have impaired CANF as compared to naturally conceived children. Method CANF was studied in 105 singletons aged 7–12 years conceived naturally (NC, N=33) or by ART (frozen embryo transfer (FET, N=34) and fresh embryo transfer (Fresh ET, N=38)). CANF was evaluated with continuous non-invasive hemodynamic measurements (Finapres®) by the HR and blood pressure changes seen relative to rest during active standing, deep breathing and Valsalva, respectively. Results The descriptive data showed no difference in CANF measurements between our study groups (Table 1). In the multivariate analysis, only the Valsalva HR-ratio to rest was significantly higher in children conceived by FET as compared to NC children after adjustments for age, sex, BMI and maternal age at delivery (Figure 1). For all meaures, the effect size (Hedges d) ranged from 0.02 to 0.48. Conclusion In this study only the Valsalva HR-response between FET and NC groups were statistically significant after adjustment for confounders, and in general effect sizes were small. Our study suggests that children conceived by ART do not have a significantly impaired cardiovascular autonomic nervous function as compared to naturally conceived children. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation

P-772 Cardiovascular autonomic nervous function in singletons conceived after ART with frozen and fresh embryo transfer compared to naturally conceived children

Abstract Study question Do children conceived after assisted reproductive technologies (ART) with frozen or fresh embryo transfer have altered cardiovascular autonomic nervous function compared to naturally conceived children? Summary answer Cardiovascular autonomic nervous function was comparable in singletons conceived after ART with frozen or fresh embryo transfer, and naturally conceived children. What is known already Cardiovascular autonomic nervous function (CANF) exert important homeostatic mechanisms to prevent major arterial blood pressure fluctuations by adjusting heart rate, cardiac contractility, and peripheral vascular tone. CANF is impaired in children with obesity and diabetes mellitus, and conductance artery stiffness is documented to influence CANF. Previous studies have reported that children conceived after ART are at risk of increased carotid intima-media thickness; insulin resistance; arterial stiffness; and hypertension. This is the first study to investigate CANF in children conceived after ART. Study design, size, duration CANF was studied in 110 singletons aged 7-12 years conceived after frozen embryo transfer (FET, N = 35), fresh embryo transfer (fresh-ET, N = 39) or natural conception (NC, N = 36). Children were born between 2009 and 2013. This study was conducted between June 2019 and October 2021. Participants/materials, setting, methods Participants were identified through the Danish IVF and Medical Birth Registries. CANF was evaluated by heart rate (HR) changes (ratio to rest) during deep breathing; Valsalva; and active stand test with continuous non-invasive hemodynamic measurements. Anthropometric measures, fasting blood samples, and maternal questionnaires were collected. Neonatal and maternal pregnancy data were collected from the Medical Birth Registry. Children with a history of congenital heart disease or mothers with gestational diabetes or diabetes mellitus were excluded. Main results and the role of chance A total of 110 singletons with a median age of 9.0 years were included in this study. We found no significant associations between conception method and our measures of CANF. For FET, fresh-ET, and NC, respectively, the HR-ratio for deep breathing was 1.62 (0.2 SD), 1.62 (0.16) and 1.63 (0.17) (ANOVA-P = 0.97). For Valsalva, the HR-ratio was 1.97 (0.4), 1.88 (0.41) and 1.63 (0.17), respectively (ANOVA-P = 0.24). For the active stand test, the HR-ratio was 1.43 (0.17), 1.41 (0.2) and 1.43 (0.19), respectively (ANOVA-P = 0.91). Associations remained non-significant after adjustment for age, sex, body surface area, body mass index, and mean arterial pressure. In the multivariate analysis, several other factors were significantly associated with HR-ratio for deep breathing: age (β = -0.06, P = 0.03), body surface area (β = 0.79, P = 0.01), body mass index (β = -0.03, P = 0.04), and mean arterial pressure (β =-0.01, P = 0.03), but not with other measures of CANF. All data for CANF were within reference limits. Also, mothers in the ART groups were older at childbirth than NC group as expected. No significant differences were observed in clinical characteristics, including neonatal and other maternal data. Limitations, reasons for caution This study is limited by its observational design to draw any firm conclusion on causality. Also, it is a limitation that the pubertal status was not systematically assessed as pubertal hormones may play a role in CANF. Wider implications of the findings This study contributes to the current knowledge about cardiovascular health risks in ART children. Reassuringly, this study found that children conceived after ART (frozen or fresh-ET) did not exhibit impaired cardiovascular autonomic nervous function compared to naturally conceived children. Trial registration number NCT03719703

Identifying clinical subtypes in sepsis-survivors with different one-year outcomes: a secondary latent class analysis of the FROG-ICU cohort

BackgroundLate mortality risk in sepsis-survivors persists for years with high readmission rates and low quality of life. The present study seeks to link the clinical sepsis-survivors heterogeneity with distinct biological profiles at ICU discharge and late adverse events using an unsupervised analysis.MethodsIn the original FROG-ICU prospective, observational, multicenter study, intensive care unit (ICU) patients with sepsis on admission (Sepsis-3) were identified (N = 655). Among them, 467 were discharged alive from the ICU and included in the current study. Latent class analysis was applied to identify distinct sepsis-survivors clinical classes using readily available data at ICU discharge. The primary endpoint was one-year mortality after ICU discharge.ResultsAt ICU discharge, two distinct subtypes were identified (A and B) using 15 readily available clinical and biological variables. Patients assigned to subtype B (48% of the studied population) had more impaired cardiovascular and kidney functions, hematological disorders and inflammation at ICU discharge than subtype A. Sepsis-survivors in subtype B had significantly higher one-year mortality compared to subtype A (respectively, 34% vs 16%, p < 0.001). When adjusted for standard long-term risk factors (e.g., age, comorbidities, severity of illness, renal function and duration of ICU stay), subtype B was independently associated with increased one-year mortality (adjusted hazard ratio (HR) = 1.74 (95% CI 1.16–2.60); p = 0.006).ConclusionsA subtype with sustained organ failure and inflammation at ICU discharge can be identified from routine clinical and laboratory data and is independently associated with poor long-term outcome in sepsis-survivors.Trial registration NCT01367093; https://clinicaltrials.gov/ct2/show/NCT01367093.Graphical