Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome.

KEY POINTS: With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation. ABSTRACT: While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17 weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25 µm (post-capillary) and ∼75 µm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α1 - (and α2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3 Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3 Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.

Computerized venous strain-gauge plethysmography is a reliable method for measuring venous function.

OBJECTIVES: To achieve reference values for computerized strain-gauge plethysmography (SGP), to assess reproducibility, and to evaluate the influence of different factors such as age, gender, body mass index, and symptomatic post-thrombotic disease on commonly used variables. METHODS: Sixty-three healthy controls and 56 patients with previous deep venous thrombosis (DVT) were included. All participants underwent computerized SGP with evaluation of outflow capacity, as well as evaluation of venous reflux and muscle pump function. RESULTS: All variables were significantly reduced in DVT limbs, both compared with contralateral limbs and with healthy controls. Only two patients had all values within normal ranges (=mean ± 2 SD in controls). Measures of outflow capacity had a coefficient of variation (CV) of 5-6% and exercise-induced volume changes a CV of 10-15%. In symptomatic post-thrombotic limbs half-refilling time was significantly related to presence of edema (R = -0.28, p < .05) and to chronic skin changes (R = -0.58, p < .001). CONCLUSIONS: We suggest that our values in healthy controls can be used as new reference values for computerized venous strain-gauge plethysmography. The computerized design ensures high reproducibility and the results indicate that this is a very useful and sensitive test for functional quantitative assessment of patients with venous disease.

Effects of low-load blood flow restriction on the venous system in comparison to traditional low-load and high-load exercises.

Purpose: Blood-Flow-Restriction (BFR) training provides the ability to achieve hypertrophy effects even though only light mechanical loads are applied. However, its impact on venous pressures and function are still unknown. Therefore, the present study investigates the influence of BFR-training on intravascular venous pressure and venous function in comparison to control exercises with low or high mechanical loads. Methods: In a randomized cross-over design, ten healthy men (27.6 ± 6.4 years) underwent three trials of unilateral knee-extensor exercise with three different training protocols, low-load- (LL-RT, 30% of the individual 1-repetition-maximum, 1RM), low-load BFR- (LL-BFR-RT, 30% 1RM, 50% limb occlusion pressure, LOP) and high-load resistance exercise (HL-RT, 75% 1RM). Exercise protocols contain about four sets of knee extension exercise (Range-of-Motion: 0-0-95°), separated by 60 s of rest. Each set was performed until volitional muscle failure. For analysis of changes in intravascular venous pressures and venous function, a venous catheter was placed at the exercising leg before each trial. Whereas venous pressures were recorded throughout the exercise trials, phlebodynamometric investigations were performed before and after each trial. Furthermore, subjective pain perception during and after exercise was accessed by visual analogue scale. One-way ANOVA was used to assess mean differences between training protocols, while two-way repeated-measures ANOVA (rANOVA; time x condition) was performed to compare changes in measures over time among conditions. Data were given as means ± standard deviation (SD). Results: In comparison to the exercise trials without venous occlusion, total workload was significantly lower in the LL-BFR-RT (LL-RT: 1745 ± 604 kg vs LL-BFR-RT: 1274 ± 237 kg vs HL-RT: 1847 ± 367 kg, p = 0.004) without indicating statistical differences in venous pressures during the exercise sets (interaction: p = 0.140) or pain perception (interaction: p = 0.574). Similarly, phlebodynamometric assessment of venous function (e.g. refill-time of the venous system pre-vs. post exercise trials-LL-RT: 29.7 ± 11.0 s vs 25.5 ± 9.6 s, LL-BFR-RT: 26.6 ± 13.0 s vs 27.3 ± 13.8 s, HL-RT: 25.9 ± 10.9 s vs 23.1 ± 8.2 s) revealed no time (p = 0.156), condition effect (p = 0.802) or their interactions (p = 0.382). Conclusion: The present study is the first one describing the acute effects of LL-BFR-RT to muscle failure on venous pressures and function in comparison to a LL- and HL-RT in the lower limbs. In contrast to the existing literature, LL-BFR-RT does not elevate the venous pressures during exercise higher than a comparative exercise without BFR and does not show any adverse effects on venous function after the exercise.

[Diagnosis of chronic venous insufficiency]. / Diagnostische Verfahren bei chronischer venöser Insuffizienz.

For the treatment of chronic venous insufficiency (CVI), various therapeutic options are available. In addition to conservative compression therapy, classical vein surgery, sclerotherapy and endoluminal therapies are increasingly being used to treat varicose veins. For a differentiated indication and correct treatment planning, a stepwise diagnosis with clinical examination and documentation of typical symptoms, dynamic vein function measurement to assess the global venous status as well as a qualitative assessment of the exact insufficient vein segments by means of color-coded duplex sonography is required. Due to the non-invasiveness of the examination and the good assessability of therapeutically relevant parameters such as anatomic conditions, diameter, and reflux of insufficient veins, color-coded duplex sonography is considered the gold standard for imaging diagnostics.

Improvement of dynamic venous function after thermal ablation with steam vein occlusion - 6-weeks and 1-year follow-up after 167 treatments.

BACKGROUND: In this paper, the method of steam vein occlusion for the treatment of the great/small saphenous vein (GSV/SSV) was analyzed in terms of a therapeutic influence on the dynamic parameters of global vein function, its effects on subjective symptoms based on chronic venous insufficiency (CVI) and the side effects of the steam vein sclerosis (SVS). It has been questioned whether the effects of this method lead to a recommendation for routine clinical practice. METHODS: The venous drainage and the venous refilling time (T0) of the leg treated were determined by photoplethysmography (Elcat, Wolfratshausen, Germany) before, six weeks and one year after the intervention to examine the effects on global venous function. Further changes of clinical symptoms and findings were assessed by the Venous Clinical Severity Score (VCSS), preoperatively and after one year, and the complication rate at 6-week follow-up was monitored. RESULTS: The SVS was performed on 167 veins (GSV: 124; SSV: 43) in a total of 156 patients. Eight patients (5.1%) did not attend the 6-week follow-up, while 29 patients (18.6%) were lost in the 1-year follow-up. Patients were suffering from symptoms such as leg pain and leg edema, which resulted in a VCSS of 9.4 (cumulated mean score of all patients) preoperatively. The T0 was reduced to mean values of 20.6 s (GSV cohort) and 21 s (SSV cohort). The VCSS improved to 6.0 after one year. This correlated with the hemodynamic parameters. The T0 increased in the GSV cohort after six weeks to 31.8 s, p < 0.001, and showed a nonsignificant improvement to 32.2 s, p = 0.509, in the 1-year check. The T0 also increased in the SSV cohort significantly after 6 weeks to 30.1 s, p < 0.001, and showed a nonsignificant reduction after one year, p = 0.289. A total of 71%of the GSV and 69.8%of the SSV of the patients involved no complications following the treatment. Light complications (grade 1) occurred (reddening, hematoma, hyperpigmentation) in the majority: 24.2%of the GSV and 18.6%of the SSV. We noticed one grade 3 complication with thrombosis in the SSV cohort, which led to a pulmonary embolism. Forty-seven complete questionnaires were analyzed (responder rate: 28.1%); 40.4%of the patients had light complaints after the treatment, such as pain, warmth or local pressure sensations (Fig. 7); 63%of those patients noticed only slight pain at a maximum of 3 out of 10. The majority (91%) would recommend this procedure. CONCLUSION: The SVS revealed endoluminal catheter-based intervention to abolish venous reflux of the G/SSV as safe. As one therapeutic target is to eliminate venous reflux, effectiveness of a method cannot be based on sonographic data alone; one must further assess patients' symptoms and dynamic venous function. This data shows an improvement of patients' symptoms which correlated well with the improvement of the venous function in digital photoplethysmography. The SVS can be recommended as a catheter-based treatment in the future.

Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction.

AIMS: Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF. METHODS AND RESULTS: Subjects with HFpEF (n = 62) and non-cardiac dyspnoea (NCD) (n = 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward-shifted central venous pressure-dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P < 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r = 0.77, P < 0.0001) and inversely correlated with right ventricular-pulmonary arterial coupling (r = -0.57, all P < 0.0001). CONCLUSIONS: Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular-pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity-related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.

Upper arm venous compliance and fitness in stable coronary artery disease patients and healthy controls.

OBJECTIVES: Arteries have been examined extensively in coronary artery disease (CAD), while less attention has been paid to veins. AIMS: (1) To determine whether venous compliance or venous outflow in the upper arm is reduced in CAD patients compared to healthy age- and fitness-matched controls; and (2) to examine the association between upper arm venous compliance and total blood volume. DESIGN: Fifteen patients with stable CAD (age 62·1 ± 5·7 years, body mass index 26·5 ± 3·2 kg·m2 , fat-free mass 59·3 ± 7·6 kg, mean arterial pressure 98·9 ± 8·0 mmHg, VO2peak : 2·92 ± 0·53 l min-1 ) were compared to twelve healthy age- and fitness-matched controls (age 62·2 ± 3·7 years, body mass index 26·2 ± 2·3 kg m2 , fat-free mass 61·0 ± 9·2 kg, mean arterial pressure 96·5 ± 9·1 mmHg, VO2peak : 3·24 ± 0·48 l min-1 ). Venous compliance was examined using high-resolution ultrasound and Doppler in the basilic vein. Blood volumes were measured by the optimized CO rebreathing method. RESULTS: Equal upper arm venous compliance normalized to blood volume (patients: 0·28 ± 0·26 mm3  mmHg-1  l-1 , healthy controls: 0·16 ± 0·11 mm3 mmHg-1  l-1 ) and peak venous outflow normalized to blood volume (patients: 10·4 ± 3·9 cm s-1  l-1 , healthy controls: 8·3 ± 0·8 cm s-1  l-1 ) were found in patients with CAD and healthy age- and fitness-matched controls. Additionally, no difference was found in blood volume (patients: 6·06 ± 0·79 l, healthy controls: 6·68 ± 1·27 l) or VO2peak . CONCLUSION: Comparable upper arm venous compliance and venous outflow in CAD patients and healthy age- and fitness-matched controls might indicate that high VO2peak and blood volume could prevent possible disease-induced reductions in venous compliance in CAD.

The influence of whole body vibration on the central and peripheral cardiovascular system.

The purpose of this study was to investigate the physiological changes of the cardiovascular system in response to whole body vibration during quiet standing and identify whether there is a greater influence on the central or peripheral cardiovascular system. Twenty healthy participants (12 male and 8 female) were assessed over two separate testing sessions for changes in peripheral skin temperature, peripheral venous function, blood flow velocity in the dorsalis pedis artery, blood pressure and heart rate during quiet standing with 40 Hz 1·9 mm synchronous vibration. Vibration exposure totalled 5 min in 1 min increments with 5 min recovery during each testing session. There were no significant changes in heart rate, blood pressure or peripheral skin temperature. Significant results were obtained for blood flow velocity with increases from 0·5 + 0·2 cm·s(-1) at baseline to 1 + 0·2 cm·s(-1) during vibration, returning to baseline levels during the recovery period. Due to the absence of changes in heart rate, blood pressure or lower leg and foot temperature, the change in blood flow velocity can be attributed to changes in peripheral vascular function. The results suggest a high level of sensitivity of the peripheral vascular system to vibration exposure; therefore, further studies should be completed to ascertain the physiological mechanisms underlying the effects of vibration on the peripheral vascular system.