Venous Stiffness Research Articles

Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model.

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development of tumor-derived endothelial cells (TECs) associated with chemoresistance. We lack specific biomarkers for TECs. Therefore, identifying new TEC biomarkers is vital for effective NB therapies. A stiffness-based platform simulating human arterial and venous stiffness was developed to study NB TECs in vitro. Adrenergic cells cultured on arterial-like stiffness transdifferentiated into TECs, while mesenchymal state cells did not. The TECs derived from adrenergic cells served as a model to explore new biomarkers, with a particular focus on GB3, a glycosphingolipid receptor implicated in angiogenesis, metastasis, and drug resistance. Notably, the TECs unequivocally expressed GB3, validating its novelty as a marker. To explore targeted therapeutic interventions, nanoparticles functionalized with the non-toxic subunit B of the Shiga toxin were generated, because they demonstrated a robust affinity for GB3-positive cells. Our results demonstrate the value of the stiffness-based platform as a predictive tool for assessing NB aggressiveness, the discovery of new biomarkers, and the evaluation of the effectiveness of targeted therapeutic strategies.

Understanding heterogeneous mechanisms of heart failure with preserved ejection fraction through cardiorenal mathematical modeling.

In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.

Norma: Participant 1,001 and the Value of Clinical Research.

Norma: Participant 1,001 and the Value of Clinical Research.

Cortical actin regulation modulates vascular contractility and compliance in veins.

Most cardiovascular research focuses on arterial mechanisms of disease, largely ignoring venous mechanisms. Here we examine ex vivo venous stiffness, spanning tissue to molecular levels, using biomechanics and magnetic microneedle technology, and show for the first time that venous stiffness is regulated by a molecular actin switch within the vascular smooth muscle cell in the wall of the vein. This switch connects the contractile apparatus within the cell to adhesion structures and facilitates stiffening of the vessel wall, regulating blood flow return to the heart. These studies also demonstrate that passive stiffness, the component of total stiffness not attributable to vascular smooth muscle activation, is severalfold lower in venous tissue than in arterial tissue. We show here that the activity of the smooth muscle cells plays a dominant role in determining total venous stiffness and regulating venous return. The literature on arterial mechanics is extensive, but far less is known about mechanisms controlling mechanical properties of veins. We use here a multi-scale approach to identify subcellular sources of venous stiffness. Portal vein tissue displays a severalfold decrease in passive stiffness compared to aortic tissues. The α-adrenergic agonist phenylephrine (PE) increased tissue stress and stiffness, both attenuated by cytochalasin D (CytoD) and PP2, inhibitors of actin polymerization and Src activity, respectively. We quantify, for the first time, cortical cellular stiffness in freshly isolated contractile vascular smooth muscle cells using magnetic microneedle technology. Cortical stiffness is significantly increased by PE and CytoD inhibits this increase but, surprisingly, PP2 does not. No detectable change in focal adhesion size, measured by immunofluorescence of FAK and zyxin, accompanies the PE-induced changes in cortical stiffness. Probing with phospho-specific antibodies confirmed activation of FAK/Src and ERK pathways and caldesmon phosphorylation. Thus, venous tissue stiffness is regulated both at the level of the smooth muscle cell cortex, via cortical actin polymerization, and by downstream smooth muscle effectors of Src/ERK signalling pathways. These findings identify novel potential molecular targets for the modulation of venous capacitance and venous return in health and disease.

Peripheral Vascular Adaptation and Orthostatic Tolerance in Fontan Physiology

The Fontan circulation is critically dependent on elevated venous pressures to sustain effective venous return. We hypothesized that chronically increased systemic venous pressures lead to adaptive changes in regional and peripheral vessels to maintain cardiac output, especially when patients are upright. Nine post-Fontan procedure patients (aged 13 to 24 years) and 6 age- and sex-matched controls were compared with techniques to measure circulatory responses (peripheral and compartmental blood flow, venous capacity, and microvascular filtration). Parameters studied included strain-gauge plethysmography measures of peripheral circulatory function, regional blood volume distribution by impedance plethysmography, and head-up tilt testing. Important differences between Fontan patients and controls were seen in several vascular compartments: (1) Calf capacitance was lower (median, 3.5 versus 5.5 mL/100 mL tissue; P=0.005), and resting venous pressure was higher (13.0 versus 10.5 mm Hg; P=0.004); (2) higher leg arterial resistance was observed (32.1 versus 22.2; P=0.03); (3) microvascular filtration pressures and threshold for edema were elevated; and (4) with head-up tilt testing, splanchnic flow was not reduced in Fontan patients versus controls (fractional change, +4% versus -32%; P=0.004), and splanchnic arterial resistance did not increase as expected (fractional change, +8% versus +79%; P=0.003). Reduced venous compliance and increased filtration thresholds may act as adaptive mechanisms in maintaining venous return in Fontan circulation. Well-compensated Fontan subjects demonstrate superior orthostatic tolerance resulting from decreased compartmental fluid shifts in response to head-up tilt and higher vascular resistance. This results from increased venous stiffness and decreased splanchnic capacitance and may also be an adaptive mechanism to maintain venous return in these patients while standing.

Sodium Intake and Vascular Stiffness in Hypertension

The relationship between sodium and blood pressure (BP) continues to be the focus of intense research. In humans, the impact of sodium on systolic BP (SBP), diastolic BP (DBP), mean BP, and pulse pressure (PP) is currently thought to be quite similar for the 4 pressures and to occur practically with identical consequences (see reviews1–8). In this review, the effect of sodium on SBP is taken into consideration mainly for a very simple but important reason: in recent years, SBP and PP have become the parameters the most difficult to control in hypertensive subjects, which is the principal goal of most antihypertensive drugs.1 Central (aortic) SBP is a complex parameter that is influenced both by cardiac (stroke volume and ventricular ejection) and vascular (arterial and venous stiffness and wave reflections) factors.1 Stroke volume, the ratio between cardiac output and heart rate, depends not only on cardiac structure and function but also on venous return. Through the extracellular and intravascular spaces and their elastic properties, stroke volume and, hence, SBP are strongly associated with sodium balance, ie, with the relationship between sodium intake and its urinary elimination, and, finally, the traditional pressure-diuresis mechanism.4 This pathway, which mainly affects the venous circulation, requires a low and steady BP, together with a vast storage capacity for salt and water. Another important pathway affects the high-pressure pulsatile arterial system, in which the SBP level is achieved through increased arterial stiffness and disturbed wave reflections. These hemodynamic parameters are strongly influenced by sodium intake, and their anomalies are mostly seen in subjects >50 years old.1,2,5,7,9 Note that, in humans, the volume and elasticity of the arterial space are very low compared with the corresponding values for the venous system.1 We have 2 principal aims for this review. First, how …

A three-parameter model for the venous pressure volume relation of the lower leg

Objectives: To derive a three-parameter model for the curvilinear venous pressure volume relation of the lower leg, and to test its consistency. Methods: A model with venous pressure at rest (P0, mmHg), the venous compliance at P0 (C0, %/mmHg) and the venous stiffness constant ( k, 1/%) was derived. With strain gauge plethysmography the venous pressure volume relations of both legs at the mid-calf and at the ankle region were measured and fitted in 120 consecutive patients in the supine position. Results: No difference was observed between the mid-calf P0 (right 8.1 ± 2.2, left 8.4 ± 2.1) nor between ankle P0 (right 10.1 ± 2.3, left 10.0 ± 2.1). A significant pressure difference of -1.8 mmHg was found between mid-calf and ankle. Leg side differences were not observed for either C0 at the ankle (right 0.36 ± 0.29, left 0.49 ± 0.85) or in the mid-calf region (right 0.54 ± 1.1, left 0.46 ± 1.0). Differences for the leg region but not for the leg side were found for k (mid-calf right 0.54 ± 0.38, left 0.64 ± 0.52, ankle right 1.32 ± 0.66 and left 1.33 ± 0.65). Conclusion: The model demonstrated provided a proper description of the curvilinear venous pressure volume relation.

Forearm venous distensibility in relation to severity of symptoms and hemodynamic data in patients with congestive heart failure.

The distensibility of the forearm veins in 24 patients with congestive heart failure was studied by occlusion plethysmography. Relationships between forearm venous distensibility and symptoms, hemodynamic data obtained by right heart catheterization and plasma levels of vasoactive hormones were evaluated. Forearm venous pressure (VP) and volume change (delta V) were measured simultaneously by the venous occlusion technique with strain gauge plethysmography. The relationship between venous pressure and volume change was fitted by the equation VP = c* exp (k* delta V) (r = 0.98 +/- 0.01) and the venous stiffness constant (k) was calculated. Venous volume change at a venous pressure of 20 mmHg (V20) was also measured as another index of venous compliance. The pressure-volume curve of the peripheral veins shifted leftward on the volume axis and the stiffness constant (k) increased as the New York Heart Association functional class grade increased. Mean pulmonary arterial pressure and pulmonary vascular resistance were closely related to k (r = 0.74, p less than 0.001; r = 0.73, p less than 0.001, respectively), and less closely to V20 (r = -0.56, p less than 0.004; r = -0.59, p less than 0.002, respectively). K and V20 were also related to stroke index (r = -0.57, p less than 0.004; r = 0.44, p less than 0.03, respectively) and stroke work index (r = -0.47, p less than 0.02; r = 0.45, p less than 0.03, respectively). K was also related to heart rate (r = 0.55, p less than 0.007), pulmonary capillary wedge pressure (r = 0.54, p less than 0.02), right atrial pressure (r = 0.51, p less than 0.02), cardiac index (r = -0.45, p less than 0.03), and systemic vascular resistance (r = 0.45, p less than 0.03). Both indexes were related to the plasma level of norepinephrine (r = 0.64, p less than 0.008; r = -0.52, p less than 0.04, respectively). We concluded that the venous tone was related to the severity of heart failure, especially to the symptoms, pulmonary arterial pressure and plasma concentration of norepinephrine, and that the venous stiffness constant, k, was a better parameter with which to assess peripheral venous tone.

Acute Hemodynamic Effects of Nilvadipine, a New Calcium Channel Blocker, in Patients with Congestive Heart Failure

The acute hemodynamic effects of nilvadipine, a newly synthesized calcium channel blocker, were studied in 12 patients with congestive heart failure. Hemodynamic measurements were made before and 15, 30, and 60 min after oral administration of 6 mg nilvadipine. Substantial reductions in systemic vascular resistance (-28.8 +/- 6.3%, p less than 0.01) and forearm vascular resistance (-52.0 +/- 6.2%, p less than 0.01) after nilvadipine administration were associated with increases in cardiac index (31.1 +/- 8.3%, p less than 0.01) and forearm blood flow (105.2 +/- 27.4%, p less than 0.01). Mean arterial and pulmonary arterial pressures were decreased by 12.2 +/- 3.0% (p less than 0.01) and 14.7 +/- 5.0% (p less than 0.05), respectively, after nilvadipine administration; however, heart rate remained unchanged. Decreases in mean arterial pressure correlated with the baseline arterial pressure (y = 0.58x - 41.6, r = 0.75, p less than 0.01). Pulmonary capillary wedge pressure decreased by 33.1 +/- 9.1% (p less than 0.01) after nilvadipine administration. However, right atrial pressure and the venous stiffness constant remained unchanged, and the venous pressure-volume curve was not shifted significantly. Therefore, the decrease in pulmonary capillary wedge pressure was attributed primarily to afterload reduction. Nilvadipine holds promise as a vasodilator for the therapy of congestive heart failure.

Lack of venodilative activity of alpha human atrial natriuretic polypeptide in patients with congestive heart failure.

We studied the effect of alpha human atrial natriuretic polypeptide (hANP) on venous vessels by occlusion plethysmography in 7 patients with congestive heart failure. In another 8 patients the effect of nitroglycerin was studied to validate the methodology. Forearm venous pressure (VP) and volume change (delta V) were measured simultaneously. The relationship between venous pressure and volume change was described by the equation VP = C x e(K x delta V) (r = 0.98 +/- 0.01) and the venous stiffness constant (K) was calculated. Alpha human atrial natriuretic polypeptide (0.1 microM/kg/min) was infused intravenously at a dose sufficient to cause arteriodilation. The pressure-volume curve of the peripheral veins was shifted rightward on the volume axis and the stiffness constant (K) was decreased (-28.1%, p less than 0.03) significantly by nitroglycerin. Alpha human atrial natriuretic polypeptide significantly decreased systemic vascular resistance but did not shift the pressure-volume curve of the vein nor did it decrease the stiffness constant (K). We conclude that hANP has far less venodilating effect than arteriodilating effect in congestive heart failure patients.

Pathophysiology and evaluation of severity of congestive heart failure on the basis of venous characteristics.

To elucidate the possibility of grading the severity of congestive heart failure by using venous characteristics, we constructed venous pressure-volume curves (PVR) and calculated venous stiffness constants (K). In addition, effects of vasoactive drugs on venous distensibility were studied. A venous pressure-volume curve could be fit well by an exponential curve (r = 0.98 +/- 0.01). The PVR was shifted to the left with an increase in the clinical severity of congestive heart failure. The exponent of these curves, K, increased as the PVR was shifted to the left. K correlated with heart rate (r = 0.52, p less than 0.01), right atrial pressure (r = 0.54, p less than 0.02) and mean pulmonary arterial pressure (r = 0.47, p less than 0.04). Nitroglycerin and amrinone dilated veins and decreased K by 19.6 +/- 6.9% (p less than 0.03) and 14.0 +/- 4.3% (p less than 0.02), respectively. Changes in K (delta K) during the nitroglycerin and amrinone infusions correlated closely with the baseline K (delta K = -0.41 K + 0.22, r = 0.92, p less than 0.01). Therefore, the venodilating effects of these drugs were greater in patients with more severe congestive heart failure. The venous stiffness constant could be useful to grade the severity of congestive heart failure.