Goal: The goal of this study is to investigate the application of fractional-order calculus in modeling arterial compliance in human vascular aging. Methods: A novel fractional-order modified arterial Windkessel model that incorporates a fractional-order capacitor (FOC) element is proposed to capture the complex and frequency-dependent properties of arterial compliance. The model\'s performance is evaluated by verifying it using data collected from three different human subjects, with a specific focus on aortic pressure and flow rates. Results: The results show that the FOC model accurately captures the dynamics of arterial compliance, providing a flexible means to estimate central blood pressure distribution and arterial stiffness. Conclusions: This study demonstrates the potential of fractional-order calculus in advancing the modeling and characterization of arterial compliance in human vascular aging. The proposed FOC model can improve our understanding of the physiological changes in arterial compliance associated with aging and help to identify potential interventions for age-related cardiovascular diseases.

Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .

The aim of this study was to determine the effect of posture changes on vascular compliance in intracranial (brain) versus extracranial vascular beds (forearm). Eighteen young adults (nine females) performed a supine-to-seated-to-standing protocol involving 5 min of rest in each position. Continuous blood pressure, middle cerebral artery (MCA) blood velocity, and brachial artery blood velocity were recorded at each posture. Three to five consecutive steady-state cardiac cycles at each posture were analyzed by a four-element lumped parameter modified Windkessel model to calculate vascular compliance. Mean arterial pressure (MAP) increased from supine to seated (76(9) vs. 81(12) mmHg; P = 0.006) and from supine to standing (76(9) vs. 82(13) mmHg; P = 0.034). Mean blood flow was greater in the MCA relative to the forearm (forearm: 40(5) mL·min-1, MCA: 224(17) mL·min-1; main effect P < 0.001). Conversely, vascular resistance (forearm: 3.25(0.50) mmHg-1·mL·min-1, brain: 0.36(0.04) mmHg-1·mL·min-1; main effect P < 0.001) and compliance (forearm: 0.010(0.001) mL·min-1·mmHg-1, brain: 0.005(0.001) mL·min-1·mmHg-1; main effect P = 0.001) were greater in the forearm compared to the brain. Significant main effects of posture were observed with decreasing values in upright positions for mean blood flow (P = 0.001) in both vascular beds, but not for resistance (P = 0.163) or compliance (P = 0.385). There were no significant interaction effects between vascular bed and posture for mean flow (P = 0.057), resistance (P = 0.258), or compliance (P = 0.329). This study provides evidence that under steady-state conditions, posture does not affect cerebrovascular compliance.

In bivalves and gastropods, ventricle contraction causes a negative pressure in the auricles and increases venous return from the afferent oblique vein (AOV): the constant-volume (CV) mechanism. The flow in the AOV should be a pulsative flow synchronized with the ventricular contraction. The flow in the heart and adjacent vessels of Mytilus galloprovincialis were measured by magnetic resonance imaging to confirm this hypothesis. Under a regular heartbeat, pulsative flows in the AOV and branchial vessels (BVs) were almost completely synchronized with the flow in the aorta, while filling of the ventricle was in the opposite phase. Flows in the BVs were directed to the posterior direction, and a pair of BVs in the gill axes (the efferent BVs) were connected to the AOV. Based on the images of the whole pathway of the AOV in an oblique slice, we confirmed that haemolymph flow was evoked from the efferent BVs and flow into the ventricle via the auricle was completed in a single heartbeat. Therefore, the walls of the AOV and BVs could resist negative transmural pressure caused by the ventricular contraction. In conclusion, the auricle, the AOV and the BVs, including the gill filaments, act as a suction pump. The pulsative venous return is driven by the negative pressure of the AOV as in the CV mechanism, and the negative pressure in the efferent BVs could draw haemolymph from the sinus via the gill and the afferent BVs. Therefore, Mytilus can start and stop its heartbeat as necessary.

We have reviewed the development and current status of therapies based on exposure to non-ionizing radiation (with a photon energy less than 10 eV) aimed at suppressing the venous neointimal hyperplasia, and consequentially at avoiding stenosis in arteriovenous grafts. Due to the drawbacks associated with the medical use of ionizing radiation, prominently the radiation-induced cardiovascular disease, the availability of procedures using non-ionizing radiation is becoming a noteworthy objective for the current research. Further, the focus of the review was the use of such procedures for improving the vascular access function and assuring the clinical success of arteriovenous fistulae in hemodialysis patients. Following a brief discussion of the physical principles underlying radiotherapy, the current methods based on non-ionizing radiation, either in use or under development, were described in detail. There are currently five such techniques, including photodynamic therapy (PDT), far-infrared therapy, photochemical tissue passivation (PTP), Alucent vascular scaffolding, and adventitial photocrosslinking. The last three are contingent on the mechanical stiffening achievable by the exogenous photochemical crosslinking of tissular collagen, a process that leads to the decrease of venous compliance. As there are conflicting opinions on the role of compliance mismatch between arterial and venous conduits in a graft, this aspect was also considered in our review.

We aimed to determine the influence of ischemic heart disease (IHD) and cardiac rehabilitation (CR) on cerebrovascular compliance index (Ci). Eleven (one female) patients with IHD (mean[SD]: 61[11] yr, 29[4] kg/m2) underwent 6 mo of CR, which consisted of ≥3 sessions/wk of aerobic and resistance training (20-60 min each). Ten (three female) similarly aged controls (CON) were tested at baseline as a comparator group. Middle cerebral artery velocity (MCAv) and mean arterial pressure were monitored continuously using transcranial Doppler ultrasound and finger photoplethysmography, respectively, during a rapid sit-to-stand maneuver. A Windkessel model was used to estimate cerebrovascular Ci every five cardiac cycles for a duration of 30 s. Cerebrovascular resistance was calculated as the quotient of MAP and MCAv. Two-way ANOVAs were used to determine whether cerebrovascular variables differ during postural transitions between groups and after CR. Baseline MCAv was higher in CON versus IHD (P = 0.014) and a time × group interaction was observed (P = 0.045) where MCAv decreased more in CON after standing. Compared with the precondition, CR had no effect on MCAv (condition P = 0.950) but a main effect of time indicated that MCAv decreased from the seated position in both conditions (time P = 0.013). Baseline cerebrovascular Ci was greater in IHD versus CON (P = 0.049) and the peak cerebrovascular Ci during the transition to standing was significantly higher in IHD compared with CON (interaction P = 0.047). CR did not affect cerebrovascular compliance (P = 0.452) and no time-by-condition interaction upon standing was present (P = 0.174). Baseline cerebrovascular Ci is higher in IHD at baseline compared with CON, but 6 mo of CR did not modify the transient increase in cerebrovascular Ci during sit-to-stand maneuvers.NEW & NOTEWORTHY Post-cardiac event cognitive impairment is common and exercise-based rehabilitation may be an effective intervention to mitigate cognitive decline. Microvascular damage due to high blood pressure pulsatility entering the brain is the putative mechanism of vascular dementia. Whether patients with ischemic heart disease exhibit lower cerebrovascular compliance, and if cardiac rehabilitation can improve cerebrovascular compliance is unknown. We observed that patients with ischemic heart disease have paradoxically higher cerebrovascular compliance, which is not affected by cardiac rehabilitation.

OBJECTIVE: Endothelial dysfunction and arterial stiffness are hallmarks of hypertension, and major risk factors for cardiovascular disease. BPH/2J (Schlager) mice are a genetic model of spontaneous hypertension, but little is known about the vascular pathophysiology of these mice and the region-specific differences between vascular beds. Therefore, this study compared the vascular function and structure of large conductance (aorta and femoral) and resistance (mesenteric) arteries of BPH/2J mice with their normotensive BPN/2J counterparts.
METHODS: Blood pressure was measured in BPH/2J and BPN/3J mice via pre-implanted radiotelemetry probes. At endpoint, vascular function and passive mechanical wall properties were assessed using wire and pressure myography, qPCR and histology.
RESULTS: Mean arterial blood pressure was elevated in BPH/2J mice compared to BPN/3J controls. Endothelium-dependent relaxation to acetylcholine was attenuated in both the aorta and mesenteric arteries of BPH/2J mice, but through different mechanisms. In the aorta, hypertension reduced the contribution of prostanoids. Conversely, in the mesenteric arteries, hypertension reduced the contribution of both nitric oxide and endothelium-dependent hyperpolarization. Hypertension reduced volume compliance in both femoral and mesenteric arteries, but hypertrophic inward remodelling was only observed in the mesenteric arteries of BPH/2J mice.
CONCLUSIONS: This is the first comprehensive investigation of vascular function and structural remodelling in BPH/2J mice. Overall, hypertensive BPH/2J mice exhibited endothelial dysfunction and adverse vascular remodelling in the macro- and microvasculature, underpinned by distinct region-specific mechanisms. This highlights BPH/2J mice as a highly suitable model for evaluating novel therapeutics to treat hypertension-associated vascular dysfunction.

Women who experience hypertension in pregnancy have increased risk of both chronic hypertension and dementia. High blood pressure is associated with increased evidence of white matter hyperintensities (WMH) in brain imaging. WMH are disruptions of the white matter of the brain that occur with demyelination and axonal degeneration, are associated with vascular disease, occur more frequently in people with hypertension, and are associated with cognitive impairment. We evaluated the relationship between WMH and subclinical cardiovascular function in healthy young nulliparous women and women with a history of early-onset preeclampsia. Sixty-two reproductive-aged women were assessed during the follicular phase of the menstrual cycle after a 3-day sodium/potassium-controlled diet. Half of participants had a history of early-onset preeclampsia, and half were nulliparous. Blood was drawn to assess inflammatory markers. Cardiovascular assessments included tonometric blood pressure monitoring, volume loading to assess vascular compliance, echocardiography to assess cardiac ejection time, brachial pulse wave velocity of the brachial artery, assessing cardiovascular stiffness, and brachial artery flow mediated vasodilation to assess endothelial mediated dilatory response. T2 fluid-attenuated inversion recovery (FLAIR) MRI imaging was obtained. Two raters, blinded to cardiovascular assessments and pregnancy history, reviewed MRI scans for evidence of WMH using the Fazekas rating scale. WMHs were detected in 17 women; 45 had normal white matter structure. Participants with Fazekas score>0 had exaggerated response to volume loading compared to women with a Fazekas score of 0 and longer cardiac ejection times. Fazekas scores >0 had lower brachial flow-mediated vasodilation and increased white blood count compared to those with no evidence of WMH. Women with WMH had reduced cardiovascular compliance, and a trend towards decreased endothelial responsiveness compared to those without WMH. These data demonstrated that the relationship between cardiovascular and brain health was detectable in young, healthy, reproductive-aged women, and may play a role in later development of clinical disease. These findings may help identify women who are at risk for cognitive decline and pathological aging.

Background: A decade ago, it became possible to derive mean systemic filling pressure (MSFP) at the bedside using the inspiratory hold maneuver. MSFP has the potential to help guide hemodynamic care, but the estimation is not yet implemented in common clinical practice. In this study, we assessed the ability of MSFP, vascular compliance (Csys), and stressed volume (Vs) to track fluid boluses. Second, we assessed the feasibility of implementation of MSFP in the intensive care unit (ICU). Exploratory, a potential difference in MSFP response between colloids and crystalloids was assessed. Methods: This was a prospective cohort study in adult patients admitted to the ICU after cardiac surgery. The MSFP was determined using 3-4 inspiratory holds with incremental pressures (maximum 35 cm H2O) to construct a venous return curve. Two fluid boluses were administered: 100 and 500 ml, enabling to calculate Vs and Csys. Patients were randomized to crystalloid or colloid fluid administration. Trained ICU consultants acted as study supervisors, and protocol deviations were recorded. Results: A total of 20 patients completed the trial. MSFP was able to track the 500 ml bolus (p < 0.001). In 16 patients (80%), Vs and Csys could be determined. Vs had a median of 2029 ml (IQR 1605-3164), and Csys had a median of 73 ml mmHg-1 (IQR 56-133). A difference in response between crystalloids and colloids was present for the 100 ml fluid bolus (p = 0.019) and in a post hoc analysis, also for the 500 ml bolus (p = 0.010). Conclusion: MSFP can be measured at the bedside and provides insights into the hemodynamic status of a patient that are currently missing. The clinical feasibility of Vs and Csys was judged ambiguously based on the lack of required hemodynamic stability. Future studies should address the clinical obstacles found in this study, and less-invasive alternatives to determine MSFP should be further explored. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03139929.

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (Ci) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm.NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.