Sympathetic-mediated blunting of forearm vasodilation is similar between young men and women

Background: The in-vivo regulation of vascular conductance (VC) is a continuous balance between endothelial vasodilation and sympathetic vasoconstriction. Although women may report blunted sympathetic vasoconstriction along with higher endothelial vasodilation than men, it is currently unknown whether the interaction between vasoconstriction and vasodilation leads to different regulation of VC between sexes. This study assessed sex differences in sympathetic-mediated blunting of endothelial vasodilation after a brief period of ischemia and whether any restriction of vasodilation blunts tissue blood flow (BF) and re-oxygenation. Methods: 13 young women and 12 young men underwent two 5-min forearm circulatory occlusions followed by reperfusion, one in basal conditions and the other during cold pressor test-induced sympathetic activation (SYMP). Brachial artery diameter and BF, mean arterial pressure, total peripheral resistance (TPR), and thenar eminence oxygenation were collected. Percent changes normalized to baseline values of forearm VC, brachial artery BF and flow-mediated dilation (FMD), TPR, and hand oxygenation after circulatory reperfusion were calculated. Results: TPR increased during SYMP in men (p = 0.019) but not in women (p = 0.967). Women showed a greater brachial artery FMD than men (p = 0.004) at rest, but sex differences disappeared after normalization to shear rate and baseline diameter (p > 0.11). The percent increases from baseline of peak and average forearm VC after circulatory reperfusion did not differ between sexes in basal conditions (p > 0.98) or during SYMP (p > 0.97), and were restrained by SYMP similarly in both sexes (p < 0.003) without impairing the hand re-oxygenation (p > 0.08) or average hyperemic response (p > 0.09). Conclusions: Although women may report blunted sympathetic vasoconstriction than men when assessed separately, the similar sympathetic-mediated restriction of vasodilation suggests a similar dynamic regulation of VC between sexes. SYMP-mediated restrictions of the normal forearm vasodilation do not impair the average hyperemic response and hand re-oxygenation in both sexes

Circadian and sex differences in carotid-femoral pulse wave velocity in young individuals and elderly with and without type 2 diabetes

The incidence of cardiovascular events is higher in the morning than in the evening and differs between sexes. We tested the hypothesis that aortic stiffness, a compelling cardiovascular risk factor, increases in the morning than in the evening in young, healthy individuals between 18 and 30 years (H18-30) or in older individuals between 50 and 80 years, either healthy (H50-80) or with type 2 diabetes (T2DM50-80). Sex differences were also investigated. Carotid-femoral pulse wave velocity (cf-PWV) recorded via Doppler Ultrasound, blood pressure and heart rate were checked at 6 a.m. and 9 p.m., at rest and during acute sympathetic activation triggered by handgrip exercise. Cf-PWV values were lower in the morning compared to the evening in all groups (p < 0.01) at rest and lower (p = 0.008) in H18-30 but similar (p > 0.267) in the older groups during sympathetic activation. At rest, cf-PWV values were lower in young women compared to young men (p = 0.001); however, this trend was reversed in the older groups (p < 0.04). During sympathetic activation, the cf-PWV was lower in women in H18-30 (p = 0.001), similar between sexes in H50-80 (p = 0.122), and higher in women in T2DM50-80 (p = 0.004). These data do not support the hypothesis that aortic stiffness increases in the morning compared to the evening within any of the considered groups in both rest and sympathetic activation conditions. There are differences between the sexes, which vary according to age and diabetes status. In particular, aortic stiffness is higher in older women than in men with diabetes during acute stress

Acute cardiovascular responses during resistance exercise: comparison between chronic heart failure patients, healthy age matched and young subjects

Acute hemodynamic responses during resistance efforts are not well characterized. The aim of the present project was to characterize such responses during lower limb resistance exercise, in different population

Preconditioning effect of heavy exercise on O2 uptake kinetics, determined as MRT (mean response time), in chronic heart failure patients

It has been demonstrated that oxygen consumption kinetics (VO2cin) at the onset of aerobic exercise may be speeded up when preceded by a short bout of heavy exercise (preconditioning heavy exercise,PHE). It was proposed that the mechanism underlying PHE be related to increased muscle blood flow and heart rate after heavy exercise, which would speed up the enhancement of oxygen transport to active muscle after PHE

Cardiac, vascular and metabolic changes during recovery from resistance effort

The aim of the present project was to characterize cardiovascular changes combined with O2 utilisation during and after resistance efforts, such as weight-lifting, in young subjects

Do the Current Guidelines for Heart Failure Diagnosis and Treatment Fit with Clinical Complexity?

Heart failure (HF) is a clinical syndrome defined by specific symptoms and signs due to structural and/or functional heart abnormalities, which lead to inadequate cardiac output and/or increased intraventricular filling pressure. Importantly, HF becomes progressively a multisystemic disease. However, in August 2021, the European Society of Cardiology published the new Guidelines for the diagnosis and treatment of acute and chronic HF, according to which the left ventricular ejection fraction (LVEF) continues to represent the pivotal parameter for HF patients’ evaluation, risk stratification and therapeutic management despite its limitations are well known. Indeed, HF has a complex pathophysiology because it first involves the heart, progressively becoming a multisystemic disease, leading to multiorgan failure and death. In these terms, HF is comparable to cancer. As for cancer, surviving, morbidity and hospitalisation are related not only to the primary neoplastic mass but mainly to the metastatic involvement. In HF, multiorgan involvement has a great impact on prognosis, and multiorgan protective therapies are equally important as conventional cardioprotective therapies. In the light of these considerations, a revision of the HF concept is needed, starting from its definition up to its therapy, to overcome the old and simplistic HF perspective

Do the current guidelines for heart failure diagnosis and treatment fit with clinical complexity?

Heart failure (HF) is a clinical syndrome defined by specific symptoms and signs due to structural and/or functional heart abnormalities, which lead to inadequate cardiac output and/or increased intraventricular filling pressure. Importantly, HF becomes progressively a multisystemic disease. However, in August 2021, the European Society of Cardiology published the new Guidelines for the diagnosis and treatment of acute and chronic HF, according to which the left ventricular ejection fraction (LVEF) continues to represent the pivotal parameter for HF patients' evaluation, risk stratification and therapeutic management despite its limitations are well known. Indeed, HF has a complex pathophysiology because it first involves the heart, progressively becoming a multisystemic disease, leading to multiorgan failure and death. In these terms, HF is comparable to cancer. As for cancer, surviving, morbidity and hospitalisation are related not only to the primary neoplastic mass but mainly to the metastatic involvement. In HF, multiorgan involvement has a great impact on prognosis, and multiorgan protective therapies are equally important as conventional cardioprotective therapies. In the light of these considerations, a revision of the HF concept is needed, starting from its definition up to its therapy, to overcome the old and simplistic HF perspective

Coherence and Coupling Functions Reveal Microvascular Impairment in Treated Hypertension

The complex interactions that give rise to heart rate variability (HRV) involve coupled physiological oscillators operating over a wide range of different frequencies and length-scales. Based on the premise that interactions are key to the functioning of complex systems, the time-dependent deterministic coupling parameters underlying cardiac, respiratory and vascular regulation have been investigated at both the central and microvascular levels. Hypertension was considered as an example of a globally altered state of the complex dynamics of the cardiovascular system. Its effects were established through analysis of simultaneous recordings of the electrocardiogram (ECG), respiratory effort, and microvascular blood flow [by laser Doppler flowmetry (LDF)]. The signals were analyzed by methods developed to capture time-dependent dynamics, including the wavelet transform, wavelet-based phase coherence, non-linear mode decomposition, and dynamical Bayesian inference, all of which can encompass the inherent frequency and coupling variability of living systems. Phases of oscillatory modes corresponding to the cardiac (around 1.0 Hz), respiratory (around 0.25 Hz), and vascular myogenic activities (around 0.1 Hz) were extracted and combined into two coupled networks describing the central and peripheral systems, respectively. The corresponding spectral powers and coupling functions were computed. The same measurements and analyses were performed for three groups of subjects: healthy young (Y group, 24.4 ± 3.4 y), healthy aged (A group, 71.1 ± 6.6 y), and aged treated hypertensive patients (ATH group, 70.3 ± 6.7 y). It was established that the degree of coherence between low-frequency oscillations near 0.1 Hz in blood flow and in HRV time series differs markedly between the groups, declining with age and nearly disappearing in treated hypertension. Comparing the two healthy groups it was found that the couplings to the cardiac rhythm from both respiration and vascular myogenic activity decrease significantly in aging. Comparing the data from A and ATH groups it was found that the coupling from the vascular myogenic activity is significantly weaker in treated hypertension subjects, implying that the mechanisms of microcirculation are not completely restored by current anti-hypertension medications

Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure

A paradox regarding the classic power spectral analysis of heart rate variability (HRV) is whether the characteristic high- (HF) and low-frequency (LF) spectral peaks represent stochastic or chaotic phenomena. Resolution of this fundamental issue is key to unraveling the mechanisms of HRV, which is critical to its proper use as a noninvasive marker for cardiac mortality risk assessment and stratification in congestive heart failure (CHF) and other cardiac dysfunctions. However, conventional techniques of nonlinear time series analysis generally lack sufficient sensitivity, specificity and robustness to discriminate chaos from random noise, much less quantify the chaos level. Here, we apply a ‘litmus test’ for heartbeat chaos based on a novel noise titration assay which affords a robust, specific, time-resolved and quantitative measure of the relative chaos level. Noise titration of running short-segment Holter tachograms from healthy subjects revealed circadian-dependent (or sleep/wake-dependent) heartbeat chaos that was linked to the HF component (respiratory sinus arrhythmia). The relative ‘HF chaos’ levels were similar in young and elderly subjects despite proportional age-related decreases in HF and LF power. In contrast, the near-regular heartbeat in CHF patients was primarily nonchaotic except punctuated by undetected ectopic beats and other abnormal beats, causing transient chaos. Such profound circadian-, age- and CHF-dependent changes in the chaotic and spectral characteristics of HRV were accompanied by little changes in approximate entropy, a measure of signal irregularity. The salient chaotic signatures of HRV in these subject groups reveal distinct autonomic, cardiac, respiratory and circadian/sleep-wake mechanisms that distinguish health and aging from CHF

Virtual Patients and Sensitivity Analysis of the Guyton Model of Blood Pressure Regulation: Towards Individualized Models of Whole-Body Physiology

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a “virtual population” from which “virtual individuals” can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the “virtual individuals” that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models