Cardiac Response Research Articles

Association between FT3 Levels and Exercise-Induced Cardiac Remodeling in Elite Athletes.

Previous studies demonstrated that variations of fT3, even within the euthyroid range, can influence cardiac function. Our aim was to investigate whether thyroid hormones, even within the euthyroid range, are associated with the magnitude of exercise-induced cardiac remodeling in Olympic athletes. We evaluated 1342 Olympic athletes (mean age 25.6 ± 5.1) practicing different sporting disciplines (power, skills, endurance, and mixed). Athletes underwent blood testing (thyroid stimulating hormone, fT3, and fT4), echocardiography, and exercise-stress testing. Athletes taking thyroid hormones, affected by thyroiditis, or presenting TSH out of ranges were excluded. The level of thyroid hormones varied according to the type of sporting discipline practiced: endurance athletes presented the lowest TSH (p < 0.0001), fT3 (p = 0.007), and fT4 (p < 0.0001) in comparison to the remaining ones. Resting heart rate (HR) was positively correlated to fT3 in athletes of different disciplines (power: p = 0.0002, R2 = 0.04; skill: p = 0.0009, R2 = 0.05; endurance: p = 0.007, R2 = 0.03; and mixed: p = 0.04, R2 = 0.01). The same results were seen for peak HR in the exercise-stress test in athletes engaged in power, skill, and endurance (respectively, p < 0.0001, R2 = 0.04; p = 0.01, R2 = 0.04; and p = 0.005, R2 = 0.02). Moreover, a positive correlation was observed with cardiac dimensions, i.e., interventricular septum (power: p < 0.0001, R2 = 0.11; skill: p = 0.02, R2 = 0.03; endurance: p = 0.002, R2 = 0.03; mixed: p < 0.0001, R2 = 0.04). Furthermore, fT3 was directly correlated with the left ventricle (LV) end-diastolic volume in skills (p = 0.04, R2 = 0.03), endurance (p = 0.04, R2 = 0.01), and mixed (p = 0.04, R2 = 0.01). Thyroid hormones, even within the euthyroid range, are associated with cardiac adaptive response to exercise and may contribute to exercise-induced cardiac remodeling.

Cardiac autonomic response to acute painful stimulus in individuals with chronic neck pain: A case-control study

PurposeCharacterize heart rate and cardiac autonomic response to painful stimulus on neck pain. MethodsTwenty-five individuals with neck pain and 25 healthy subjects were included. Heart rate variability and heart rate were assessed in the conditioned pain modulation test at pretest rest, during testing and in recovery. Heart rate variability indices were obtained using linear and nonlinear methods. ResultsNo significant differences were observed between groups regarding heart rate and the linear methods (p > 0.05). However, significant difference was observed between groups regarding nonlinear methods (standard deviation of the instantaneous variability of beat-to-beat interval variability, p = 0.005) ConclusionsIndividuals with chronic neck pain showed autonomic responses similar to those of their healthy counterparts during the conditioning stimulus.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37)and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) invitro and invivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Влияние поражения сердца на прогноз у пациентов с системным AL-амилоидозом

AIM. To assess the clinical features as well as the factors affecting prognosis and long-term treatment outcomes in systemic AL amyloidosis patients with cardiac involvement. MATERIALS &amp; METHODS. The trial enrolled 123 systemic AL amyloidosis patients with cardiac involvement who were treated at the RM Gorbacheva Scientific Research Institute in 2004–2023. The patients were 34–85 years of age (median 61 years); there were 61 women (49.6 %) and 62 men (50.4 %). RESULTS. Cardiac disease grades 1, 2, 3a, and 3b were identified in 13.8 %, 50.4 %, 17.9 %, and 17.9 % of AL amyloidosis patients, respectively. Chronic cardiac failure (CCF) developed in 65.9 % (n = 81), and severe cardiac failure was detected in 25.4 % (n = 31) of patients. Most of them (90,2 %), despite CCF, preserved left ventricular ejection fraction (&gt; 40 %) with the mean value of 59.6 % (range 33–78 %). The left ventricular stroke volume index (SVI) was below the normal values (&lt; 41 mL/m2) in 92.7 % of patients. The mean SVI value was 26.1 mL/m2 (range 8.3–49.5 mL/m2). The lower SVI was associated with cardiac disease grades. This parameter appeared to be 30.9 mL/m2, 26.8 mL/m2, 24.8 mL/m2, and 21.4 mL/m2 in grades 1, 2, 3a, and 3b (p = 0.006), respectively. Total global strain (TGS) in the left ventricle myocardium was decreased (&lt; 20 %) in 94.6 % of patients. The mean TGS value was 13.8 % (range 4.4–34.8 %). TGS was diminishing with increasing cardiac disease grade (grade 1 with 17.8 %, grade 2 with 14.6 %, grade 3a with 13.1 %, and grade 3b with 9.6 %) (p = 0.007). Atrial fibrillation was reported in 23 % of patients, supraventricular tachycardia was observed in 31.9 %, and supraventricular extrasystoles were registered in 39.7 %. Ventricular extrasystoles were found in 73.7 % of patients, and ventricular tachycardia was seen in 13.2 %. Sinoatrial block was reported in 6.6 % of patients, and atrioventricular block was identified in 19.8 %. Syncope occurred in 12.3 % of patients. An artificial cardiac pacemaker was implanted in 8 patients. The thromboembolism rate was 13 %: the myocardial infarction rate was 11.4 %, and the rate of acute cerebrovascular accidents was 5.7 %. Atrial clots were detected in 2 (1.6 %) patients. The cumulative incidence of hematologic response for 2 years was 57 % and did not depend on cardiac disease grade, the 2-year rate of cardiac response was 39.1 %. Before achieving hematologic and cardiac responses, mortality was 26.5 % and 29.9 %, respectively. The overall 5-year survival was 62.6 %, and the 5-year hematologic progression-free and major organ impairment-free survival was 39.3 %. Cox regression model confirmed 3 independent predictors of poor prognosis: the level of NT-proBNP ≥ 2500 pg/mL (p = 0.004), SVI &lt; 25 mL/m2 (p = 0.0174), and prior syncope (p = 0.0191). The achievement of hematologic response had a positive effect on survival rates (p &lt; 0.0001). CONCLUSION. A comprehensive assessment of cardiac damage by the time of primary AL amyloidosis diagnosis as well as appropriate treatment of this disease can reduce the risk of early cardiac mortality and enhance chances of not only achieving hematologic response but also improving survival rates.

Sex differences in cardiac transcriptomic response to neonatal sleep apnea.

Pediatric obstructive sleep apnea poses a significant health risk, with potential long-term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex-specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive invivo physiological assessments, including whole-body plethysmography, treadmill stress-tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age-matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex-based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH-related arrhythmia. These findings emphasize the importance of considering sex-specific responses in understanding the cardiovascular implications of pediatric sleep apnea.

Computational modeling for the quantitative assessment of cardiac autonomic response to orthostatic stress

Objective. The autonomic nervous system (ANS) plays a critical role in regulating not only cardiac functions but also various other physiological processes, such as respiratory rate, digestion, and metabolic activities. The ANS is divided into the sympathetic and parasympathetic nervous systems, each of which has distinct but complementary roles in maintaining homeostasis across multiple organ systems in response to internal and external stimuli. Early detection of ANS dysfunctions, such as imbalances between the sympathetic and parasympathetic branches or impairments in the autonomic regulation of bodily functions, is crucial for preventing or slowing the progression of cardiovascular diseases. These dysfunctions can manifest as irregularities in heart rate, blood pressure regulation, and other autonomic responses essential for maintaining cardiovascular health. Traditional methods for analyzing ANS activity, such as heart rate variability (HRV) analysis and muscle sympathetic nerve activity recording, have been in use for several decades. Despite their long history, these techniques face challenges such as poor temporal resolution, invasiveness, and insufficient sensitivity to individual physiological variations, which limit their effectiveness in personalized health assessments. Approach. This study aims to introduce the open-loop Mathematical Model of Autonomic Regulation of the Cardiac System under Supine-to-stand Maneuver (MMARCS) to overcome the limitations of existing ANS analysis methods. The MMARCS model is designed to offer a balance between physiological fidelity and simplicity, focusing on the ANS cardiac control subsystems’ input–output curve. The MMARCS model simplifies the complex internal dynamics of ANS cardiac control by emphasizing input–output relationships and utilizing sensitivity analysis and parameter subset selection to increase model specificity and eliminate redundant parameters. This approach aims to enhance the model’s capacity for personalized health assessments. Main results. The application of the MMARCS model revealed significant differences in ANS regulation between healthy (14 females and 19 males, age: 42 ± 18) and diabetic subjects (8 females and 6 males, age: 47 ± 14). Parameters indicated heightened sympathetic activity and diminished parasympathetic response in diabetic subjects compared to healthy subjects (p < 0.05). Additionally, the data suggested a more sensitive and potentially more reactive sympathetic response among diabetic subjects (p < 0.05), characterized by increased responsiveness and intensity of the sympathetic nervous system to stimuli, i.e. fluctuations in blood pressure, leading to more pronounced changes in heart rate, these phenomena can be directly reflected by gain parameters and time response parameters of the model. Significance. The MMARCS model represents an innovative computational approach for quantifying ANS functionality. This model guarantees the accuracy of physiological modeling while reducing mathematical complexity, offering an easy-to-implement and widely applicable tool for clinical measurements of cardiovascular health, disease progression monitoring, and home health monitoring through wearable technology.

Unexpected Genetic Twists in Patients with Cardiac Devices.

Objective: To assess the frequency and types of genetic mutations in patients with arrhythmias who underwent cardiac device implantation. Methods: Retrospective observational study, including 38 patients with different arrhythmias and cardiac arrest as a first cardiac event. Treatment modalities encompass pacemakers, transvenous defibrillators, loop recorders, subcutaneous defibrillators, and cardiac resynchronization therapy. All patients underwent genetic testing, using commercially available panels (106-174 genes). Outcome measures include mortality, arrhythmia recurrence, and device-related complications. Results: Clinical parameters revealed a family history of sudden cardiac death in 19 patients (50%), who were predominantly male (58%) and had a mean age of 44.5 years and a mean left ventricle ejection fraction of 40.3%. Genetic testing identified mutations in various genes, predominantly TMEM43 (11%). In two patients (3%) with arrhythmogenic cardiomyopathy, complete subcutaneous defibrillator extraction with de novo transvenous implantable cardioverter-defibrillator implantation was needed. The absence of multiple associations among severe gene mutations was crucial for cardiac resynchronization therapy response. Mortality in this group was around 3% in titin dilated cardiomyopathy patients. Conclusions: Integration of genetic testing into the decision-making process for patients with electronic devices represents a paradigm shift in personalized medicine. By identifying genetic markers associated with arrhythmia susceptibility, heart failure etiology, and cardiac resynchronization therapy response, clinicians can tailor device choices to optimize patient outcomes.

Boosting arousal and cognitive performance through alternating posture: Insights from a multi-method laboratory study.

This study investigated the role of arousal and effort costs in the cognitive benefits of alternating between sitting and standing postures using a sit-stand desk, while measuring executive functions, self-reports, physiology, and neural activity in a 2-h laboratory session aimed to induce mental fatigue. Two sessions were conducted with a one-week gap, during which participants alternated between sitting and standing postures each 20-min block in one session and remained seated in the other. In each block, inhibition, switching, and updating were assessed. We examined effects of time-on-task, acute (local) effects of standing versus sitting posture, and cumulative (global) effects of a standing posture that generalize to the subsequent block in which participants sit. Results (N = 43) confirmed that time-on-task increased mental fatigue and decreased arousal. Standing (versus sitting) led to acute increases in arousal levels, including self-reports, alpha oscillations, and cardiac responses. Standing also decreased physiological and perceived effort costs. Standing enhanced processing speed in the flanker task, attributable to shortened nondecision time and speeded evidence accumulation processes. No significant effects were observed on higher-level executive functions. Alternating postures also increased heart rate variability cumulatively over time. Exploratory mediation analyses indicated that the positive impact of acute posture on enhanced drift rate was mediated by self-reported arousal, whereas decreased nondecision time was mediated by reductions in alpha power. In conclusion, alternating between sitting and standing postures can enhance arousal, decrease effort costs, and improve specific cognitive and physiological outcomes.

Depressive symptoms, task choice, and effort: The moderating effect of personal control on cardiac response.

Dysphoric individuals perceive mental tasks as more demanding and show increased cardiovascular responses during the performance of easy cognitive tasks. Recent research on action shielding indicates that providing individuals with personal control over their tasks can mitigate the effects of manipulated affective states on cardiovascular responses reflecting effort. We investigated whether the shielding effect of personal choice also applies to the effect of dispositional negative mood on effort. N = 125 university students with high (dysphoric) versus low (nondysphoric) depressive symptoms engaged in an easy cognitive task either by personal choice or external assignment. As expected, dysphoric individuals showed significantly stronger cardiac PEP reactivity during task performance when the task was externally assigned. Most importantly, this dysphoria effect disappeared when participants could ostensibly personally choose their task. Our findings show that the previously observed shielding effect of personal action choice against incidental affective stimulation also applies to dispositional negative affect.

Global ischemia induces stemness and dedifferentiation in human adult cardiomyocytes after cardiac arrest

Global ischemia has been shown to induce cardiac regenerative response in animal models. One of the suggested mechanisms behind cardiac regeneration is dedifferentiation of cardiomyocytes. How human adult cardiomyocytes respond to global ischemia is not fully known. In this study, biopsies from the left ventricle (LV) and the atrioventricular junction (AVj), a potential stem cell niche, were collected from multi-organ donors with cardiac arrest (N = 15) or without cardiac arrest (N = 6). Using immunohistochemistry, we investigated the expression of biomarkers associated with stem cells during cardiomyogenesis; MDR1, SSEA4, NKX2.5, and WT1, proliferation markers PCNA and Ki67, and hypoxia responsive factor HIF1α. The myocyte nuclei marker PCM1 and cardiac Troponin T were also included. We found expression of cardiac stem cell markers in a subpopulation of LV cardiomyocytes in the cardiac arrest group. The same cells showed a low expression of Troponin T indicating remodeling of cardiomyocytes. No such expression was found in cardiomyocytes from the control group. Stem cell biomarker expression in AVj was more pronounced in the cardiac arrest group. Furthermore, co-expression of PCNA and Ki67 with PCM1 was only found in the cardiac arrest group in the AVj. Our results indicate that a subpopulation of human cardiomyocytes in the LV undergo partial dedifferentiation upon global ischemia and may be involved in the cardiac regenerative response together with immature cardiomyocytes in the AVj.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome

Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

HOVON 104, long-term follow-up of bortezomib-dexamethasone induction therapy followed by autologous stem cell transplantation in newly diagnosed AL amyloidosis patients.

The HOVON 104 studied bortezomib-dexamethasone induction therapy and autologous stem cell transplantation in 50 patients, of whom 35 received an autologous stem cell transplantation (ASCT). We demonstrate a 5-year overall survival (OS) of 73% and progression-free survival (PFS) of 52% for all 50 patients with a median follow-up of 61.3 months. For the 35 transplanted patients, calculated from the date of ASCT, the 5-year OS and PFS were 91% and 68%, respectively. After ASCT, the rate of organ response improved over time but stabilized around 3 years. A complete cardiac response was seen in around 60% of patients and remained stable from 2 years onward. Reaching complete renal response was slower over time and achieved by 61% of the renal-affected patients at 5 years. We confirm the excellent outcomes after ASCT and demonstrate a 60% complete organ response with longer follow-up.

Otud6b induces pulmonary arterial hypertension by mediating the Calpain-1/HIF-1α signaling pathway

Pulmonary hypertension (PAH) is a cardiopulmonary disease in which pulmonary artery pressure continues to rise, leading to right heart failure and death. Otud6b is a member of the ubiquitin family and is involved in cell proliferation, apoptosis and inflammation. The aim of this study was to understand the role and mechanism of Otud6b in PAH. C57BL/6 and Calpain-1 knockout (KO) mice were exposed to a PAH model induced by 10% oxygen. Human pulmonary artery endothelial cells (HPACEs) and human pulmonary artery smooth muscle cells (HPASMCs) were exposed to 3% oxygen to establish an in vitro model. Proteomics was used to determine the role of Otud6b and its relationship to Calpain-1/HIF-1α signaling. The increased expression of Otud6b is associated with the progression of PAH. ROtud6b activates Otud6b, induces HIF-1α activation, increases the production of ET-1 and VEGF, and further aggravates endothelial injury. Reducing Otud6b expression by tracheal infusion of siOtud6b has the opposite effect, improving hemodynamic and cardiac response to PAH, reducing the release of Calpain-1 and HIF-1α, and eliminating the pro-inflammatory and apoptotic effects of Otud6b. At the same time, we also found that blocking Calpain-1 reduced the effect of Otud6b on HIF-1α, and inhibiting HIF-1α reduced the expression of Calpain-1 and Otud6b. Our study shows that increased Otud6b expression during hypoxia promotes the development of PAH models through a positive feedback loop between HIF-1α and Calpain-1. Therefore, we use Otud6b as a biomarker of PAH severity, and regulating Otud6b expression may be an effective target for the treatment of PAH.Graphical

Cardiohemodynamic responses and heart rate variability following an active orthostatic test among male residents of the North with different NOS3 (rs2070744) genotypes

AIM: This study explored associations between the -786TC (rs2070744) genetic polymorphism of the NOS3 gene and the main indices of systemic hemodynamics and heart rate variability following an active orthostatic test in men living in the North. MATERIAL AND METHODS: Eighty-three healthy men aged 33.5±1.5 yеаrs on average, who were permanent residents of the Magadan Region, comprised the sample. The participants underwent both resting and active orthostatic testing modes. Cardiovascular system variables were recorded using an automatic tonometer. Hemodynamic indices were then calculated. Short-term heart rate variability in frequency and spectral areas was simultaneously measured using the Varikard hardsoft complex unit. Genotyping was conducted using polymerase chain reaction. The sample was then divided into two groups: Group 1 consisted of homozygotes with the TT genotype (n=34), while Group 2 comprised carriers of the NOS3*C allele variant (genotypes TC+CC) associated with reduced nitric oxide production (n=49). RESULTS: By examining the complex vasomotor, chrono- and inotropic reactions of hemodynamic and heart rate variables during the active orthostatic test, we were able to discern unique patterns in the response of the two groups under study. Men in Group 1 demonstrated an elevated cardiac output response during orthostatic changes, while maintaining consistent vascular resistance values. This was accompanied by a shift towards sympathetic autonomic activity and an increase in the very low-frequency component of heart rate variability. In Group 2, individuals with sympathetic insufficiency and increased vascular resistance during the orthostatic test showed a 35% increase in the low-frequency component of the cardiac rhythm reflecting the importance of this indicator as a stimulator of blood pressure rhythm fluctuations mediated by baroreflex mechanisms. CONCLUSION: Our findings suggest that men lacking the NOS3*С allele variant in their genotype demonstrate more favorable responses to the active orthostatic test. This may reflect higher level of cardiovascular functional reserves. The 786TC (rs2070744) polymorphism of the NOS3 gene can be considered as a marker of cardiohemodynamic status and autonomic regulations during functional exercise, such as an active orthostatic test.

Phillyrin improves myocardial remodeling in salt-sensitive hypertensive mice by reducing endothelin1 signaling.

Prolonged exposure to chronic hypertension places the heart under excessive strain, resulting in myocardial remodeling. Phillyrin, derived from the natural plant Forsythia suspensa, has been found to possess cardioprotective properties. The objective of this study is to investigate the role and mechanism of phillyrin in hypertension-induced myocardial remodeling in mice. We constructed a mouse model of salt-sensitive hypertension. The mice were treated with varying doses of phillyrin, and their blood pressure, cardiac function, cardiac hypertrophy, fibrosis, inflammation, and other conditions were assessed. Our research findings demonstrated that phillyrin has the potential to lower blood pressure, enhance cardiac function, and mitigate cardiac hypertrophy, fibrosis, and inflammatory responses in deoxycorticosterone acetate-salt hypertension mice. In hypertensive mice, there was an elevated expression of endothelin1 (ET-1) in heart tissue, which can be reduced by phillyrin. Additionally, phillyrin effectively reduced the hypertrophy of H9c2 cells induced by ET-1 stimulation. Our research highlights the therapeutic capabilities of phillyrin in the treatment of myocardial remodeling through the reduction of ET-1 signaling. These results contribute to the advancement of novel applications for phillyrin and establish a solid conceptual basis for future investigations in this area.

Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults

BackgroundThe amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. MethodsWe studied healthy older adult participants (N = 21, ages 48–79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. ResultsSignificant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. ConclusionsThe results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.

Patients with a cardiac complete response in AL amyloidosis have survival rates similar to those of a matched general population

AbstractThe survival of patients achieving a cardiac complete response in light chain amyloidosis, defined as N-terminal pro B-type natriuretic peptide ≤350 pg/mL or B-type natriuretic peptide ≤80 pg/mL, was similar to that of a matched general population, with estimated 5-year survival rates of 93% and 95%, respectively.

Exploring the contribution of inter-individual factors to the development of physiological heat strain in older adults exposed to simulated indoor overheating.

Older adults are at elevated risk of heat-related mortality due to age-associated declines in thermoregulatory and cardiovascular function. However, the inter-individual factors that exacerbate physiological heat strain during heat exposure remain unclear, making it challenging to identify more heat-vulnerable subgroups. We therefore explored factors contributing to inter-individual variability in physiological responses of older adults exposed to simulated hot weather. Thirty-seven older adults (61-80 years, 16 females) rested for 8 h in 31 and 36 °C (45% relative humidity). Core (rectal) temperature, heart rate (HR), HR variability, mean arterial pressure (MAP), and cardiac autonomic responses to standing were measured at baseline and end-exposure. Bootstrapped least absolute shrinkage and selection operator regression was used to evaluate whether variation in these responses was related to type 2 diabetes (T2D, n=10), hypertension (n=18), age, sex, body morphology, habitual physical activity levels, and/or heat-acclimatization. T2D was identified as a predictor of end-exposure HR (with vs. without: 13 beats/min (bootstrap 95% confidence interval: 6, 23)), seated MAP (-7mmHg (-18, 1)), and the systolic pressure response to standing (20mmHg (4, 36)). HR was also influenced by sex (female vs. male: 8 beats/min (1, 16)). No other predictors were identified. The inter-individual factors explored did not meaningfully contribute to the variation in body temperature responses in older adults exposed to simulated indoor overheating. By contrast, cardiovascular responses were exacerbated in females and individuals with T2D. These findings improve understanding of how inter-individual differences contribute to heat-induced physiological strain in older persons.

A real-life study of daratumumab combinations in newly diagnosed patients with light chain (AL) amyloidosis.

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.

Influence of hypercapnia and hypercapnic hypoxia on the heart rate response to apnea.

We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty-six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (-19 ± 16 bpm) than normocapnic normoxic apneas (-11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (-19 ± 15 bpm; p = 0.999) and hypercapnic apneas (-14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (-11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (-9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia.