Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the CAMEO-DAPA 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 CAMEO-DAPA trial (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.

Peripheral whole blood microRNA expression in relation to vascular function: a population-based study.

BACKGROUND: As key regulators of gene expression, microRNAs affect many cardiovascular mechanisms and have been associated with several cardiovascular diseases. In this study, we aimed to investigate the relation of whole blood microRNAs with several quantitative measurements of vascular function, and explore their biological role through an integrative microRNA-gene expression analysis. METHODS: Peripheral whole blood microRNA expression was assessed through RNA-Seq in 2606 participants (45.8% men, mean age: 53.93, age range: 30 to 95 years) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Weighted gene co-expression network analysis was used to cluster microRNAs with highly correlated expression levels into 14 modules. Through linear regression models, we investigated the association between each module's expression and quantitative markers of vascular health, including pulse wave velocity, total arterial compliance index, cardiac index, stroke index, systemic vascular resistance index, reactive skin hyperemia and white matter hyperintensity burden. For each module associated with at least one trait, one or more hub-microRNAs driving the association were defined. Hub-microRNAs were further characterized through mapping to putative target genes followed by gene ontology pathway analysis. RESULTS: Four modules, represented by hub-microRNAs miR-320 family, miR-378 family, miR-3605-3p, miR-6747-3p, miR-6786-3p, and miR-330-5p, were associated with total arterial compliance index. Importantly, the miR-320 family module was also associated with white matter hyperintensity burden, an effect partially mediated through arterial compliance. Furthermore, hub-microRNA miR-192-5p was related to cardiac index. Functional analysis corroborated the relevance of the identified microRNAs for vascular function by revealing, among others, enrichment for pathways involved in blood vessel morphogenesis and development, angiogenesis, telomere organization and maintenance, and insulin secretion. CONCLUSIONS: We identified several microRNAs robustly associated with cardiovascular function, especially arterial compliance and cardiac output. Moreover, our results highlight miR-320 as a regulator of cerebrovascular damage, partly through modulation of vascular function. As many of these microRNAs were involved in biological processes related to vasculature development and aging, our results contribute to the understanding of vascular physiology and provide putative targets for cardiovascular disease prevention.

Role of hemolysis on pulmonary arterial compliance and right ventricular systolic function after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB. METHODS: This is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014-2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB. RESULTS: PAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (-0.28 ml/mmHg, 95%CI -0.49 to -0.01, p = 0.012) and RVFI (0.14 mmHg*L-1*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments. CONCLUSION: PAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

Changes of Arterial and Venous Cerebral Blood Flow Correlation in Moderate-to-Severe Traumatic Brain Injury: A CT Perfusion Study.

We compared differences in perfusion computed tomography (PCT)-derived arterial and venous cerebral blood flow (CBF) in moderate-to-severe traumatic brain injury (TBI) as an indication of changes in cerebral venous outflow patterns referenced to arterial inflow. Moderate-to-severe TBI patients (women 53; men 74) underwent PCT and were stratified into 3 groups: I (moderate TBI), II (diffuse severe TBI without surgery), and III (diffuse severe TBI after the surgery). Arterial and venous CBF was measured by PCT in both the middle cerebral arteries (CBFmca) and the upper sagittal sinus (CBFuss). In group I, CBFmca on the left and right sides were significantly correlated with each other (p < 0.0001) and with CBFuss (p = 0.048). In group II, CBFmca on the left and right sides were also correlated (p < 0.0000001) but not with CBFuss. Intracranial pressure reactivity (PRx) and CBFuss were correlated (p = 0.00014). In group III, CBFmca on the side of the removed hematoma was not significantly different from the opposite CBFmca (p = 0.680) and was not correlated with CBFuss. Conclusions: The increasing severity of TBI is accompanied by an impairment of the correlation between the arterial and venous CBF in the supratentorial vessels suggesting shifting in arterial and venous CBF in severe TBI associated with increased ICP reflected by PRx.

Pulmonary arterial compliance in patients of CHD with increased pulmonary blood flow.

INTRODUCTION: Pulmonary arterial compliance, the dynamic component of pulmonary vasculature, remains inadequately studied in patients with left to right shunts. We sought to study the pulmonary arterial compliance in patients with left to right shunt lesions and its utility in clinical decision-making. MATERIALS AND METHODS: In this single-centre retrospective study, we reviewed cardiac catheterisation data of consecutive patients of left to right shunt lesions catheterised over one year. In addition to the various other parameters, pulmonary arterial compliance was calculated, as indexed pulmonary flow (Qpi) / (Heart rate × pulse pressure in the pulmonary artery). RC time was also calculated, as the product of pulmonary arterial compliance and pulmonary vascular resistance index. Patients were divided into "operable," "borderline," and "inoperable" based on the decision of the treating team, and the pulmonary arterial compliance values were evaluated in these groups to study if it can be utilised to refine the operability decision. RESULTS: 298 patients (Median age 16 years, 56% <18 years) with various acyanotic shunt lesions were included. Overall, the pulmonary arterial compliance varied with Qpi, pulmonary artery mean pressure, and pulmonary vascular resistance index, but did not vary with age, type of lesion, or transpulmonary gradients. The median pulmonary arterial compliance in patients with normal pulmonary artery pressure (Mean pulmonary artery pressure less than 20 mmHg) was 4.1 ml/mmHg/m2 (IQR 3.2). The median pulmonary arterial compliance for operable patients was 2.67 ml/mmHg/m2 (IQR 2.2). Median pulmonary arterial compliance was significantly lower in both inoperable (0.52 ml/mmHg/m2, IQR 0.34) and borderline (0.80 ml/mmHg/m2, IQR 0.36) groups when compared to operable patients (p < 0.001). A pulmonary arterial compliance value lower than 1.18 ml/mmHg/m2 identified inoperable patients with high sensitivity and specificity (95%, AUC 0.99). However, in borderline cases, assessment by this value did not agree with empirical clinical assessment.The median RC time for the entire study population was 0.47 S (IQR 0.30). RC time in operable patients was significantly lower than that in the inoperable patients (Median 0.40 IQR 0.23 in operable, 0.73 0.25 in inoperable patients (p < 0.001). CONCLUSIONS: Addition of pulmonary arterial compliance to the routine haemodynamic assessment of patients with shunt lesions may improve our understanding of the pulmonary circulation and may have clinical utility.

Evaluation of subclinical atherosclerosis and cardiac functions in children of mothers with gestational diabetes and maternal obesity.

BACKGROUND AND AIMS: We aimed to evaluate the effects of maternal obesity or gestational diabetes on body composition, lipid, and glucose metabolism, arterial morphology, and functions in children, and to investigate these effects in terms of cardiometabolic diseases. METHODS: The study group was composed of 48 children who had a history of gestational diabetes or maternal obesity, and the control group was composed of 33 children. Echocardiographic assessments were performed. Socio-economic status and education level of mothers were obtained. RESULTS: In the study group, carotid intima-media thickness, epicardial adipose tissue thickness, and arterial stiffness values were found to be significantly higher compared to the control group (p < 0.001, p < 0.001, p = 0.003, respectively), while arterial distensibility and arterial strain values were found to be significantly lower (p = 0.003, p = 0.008, respectively). Among the children who had similar body mass index in both groups, children in the study group had higher carotid intima-media thickness and epicardial adipose tissue thickness values. Arterial stiffness values were significantly reduced (p = 0.028) and arterial distensibility and strain values were significantly increased (p = 0.039, p = 0.033, respectively) in the children whose mothers had gestational diabetes and high socio-economic status. Left ventricular mass and left ventricular end-diastolic internal thickness were found to be significantly increased in the children who had obese and unemployed mothers (p = 0.04, p = 0.03, respectively). CONCLUSION: Low socio-economic status was found to be associated with increased maternal obesity and gestational diabetes. Poor socio-economic status, poor glycaemic control and being overweight during pregnancy indicate negative cardiometabolic outcomes for children in the long term.

The Impact of Fitness Status on Vascular and Baroreceptor Function in Healthy Women and Men.

BACKGROUND: Chronic endurance exercise training elicits desirable physiological adaptations in the cardiovascular system. The volume of exercise training required to generate healthy adaptations is unclear. This study assessed the effects of differing exercise training levels on arterial stiffness, compliance, and autonomic function. METHODS: Eighty healthy adults (38.5 ± 9.7 years; 44% female) defined as endurance-trained (ET, n = 29), normally active (NA, n = 27), or inactive (IN, n = 24) participated. Cardiovascular markers, including hemodynamics, large arterial compliance and small arterial compliance (LAC and SAC), carotid-femoral pulse wave velocity (PWV), and spontaneous baroreceptor sensitivity (BRS) were assessed. RESULTS: ET showed significantly greater LAC values (21.4 ± 6.5) than NA (16.9 ± 2.5; p = 0.002) and IN (14.7 ± 3.2 mL × mm Hg × 10; p = 0.028). Values for SAC and BRS were significantly higher in ET than IN (p < 0.001 and p = 0.028, respectively), but not NA. Compared to IN, PWV values for ET and NA were significantly lower (p < 0.003). After adjusting for covariates (age, sex, and SBP), significant associations with cardiovascular fitness status were noted for all markers but BRS. CONCLUSION: Endurance exercise increases LAC likely due to high-volume training; however, lower volumes of physical activity may be sufficient to positively benefit vascular health overall.

Impact of blood pressure on coronary perfusion and valvular hemodynamics after aortic valve replacement.

OBJECTIVE: Our objective was to evaluate the impact of various blood pressures (BPs) on coronary perfusion and valvular hemodynamics following aortic valve replacement (AVR). BACKGROUND: Lower systolic and diastolic (SBP/DBP) pressures from the recommended optimal target range of SBP < 120-130 mmHg and DBP < 80 mmHg after AVR have been independently associated with increased cardiovascular and all-cause mortality. METHODS: The hemodynamic assessment of a 26 mm SAPIEN 3 transcatheter aortic valve (TAV), 29 mm Evolut R TAV, and 25 mm Magna Ease surgical aortic valve (SAV) was performed in a pulsed left heart simulator with varying SBP, DBP, and heart rate (HR) conditions (60 and 120 bpm) at 5 L/min cardiac output (CO). Average coronary flow (CF), effective orifice areas (EOAs), and valvulo-arterial impedance (Zva) were calculated. RESULTS: At HR of 60 bpm, at SBP < 120 mmHg and DBP < 60 mmHg, CF decreased below the physiological lower limit with several different valves. Zva and EOA were found to increase and decrease respectively with increasing SBP and DBP. The same results were found with an HR of 120 bpm. The trends of CF variation with BP were similar in all valves however the drop below the lower physiological CF limit was valve dependent. CONCLUSION: In a controlled in vitro system, with different aortic valve prostheses in place, CF decreased below the physiologic minimum when SBP and DBP were in the range targeted by blood pressure guidelines. Combined with recent observations from patients treated with AVR, these findings underscore the need for additional studies to identify the optimal BP in patients treated with AVR for AS.

Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.

Studies in the gravid rat model revealed a key role for the corpus luteal hormone, relaxin, in the maternal circulatory changes of early pregnancy epitomized by profound systemic vasodilation and increased arterial compliance. To determine whether the corpus luteum may play a similar role in human pregnancy, women who conceived by in vitro fertilization were studied. Implementation of artificial (programmed) cycles for embryo transfers, which precluded the formation of a corpus luteum, was associated with notable attenuation of the gestational rise in cardiac output and fall in carotid-femoral pulse wave velocity (reflecting impairment of arterial dilation and increased compliance, respectively) and deficiencies in other cardiovascular changes normally observed during the first trimester. Cardiac output and carotid-femoral pulse wave velocity were restored after the first trimester of pregnancy, consistent with rescue by placental vasodilators, such as placental growth factor. In addition, a potential role of corpus luteal factors in reducing the risk of developing preeclampsia was hypothesized. In most single and multiple center, prospective and retrospective cohort (and registry) studies, the risk of developing preeclampsia and preeclampsia with severe features was increased specifically in women undergoing autologous frozen embryo transfer in artificial cycles without the formation of a corpus luteum relative to natural, modified natural, stimulated, or controlled ovarian stimulation cycles and spontaneous pregnancies-all associated with the formation of at least 1 corpus luteum. Taken together, these observational studies are sufficiently compelling to warrant randomized clinical trials comparing preeclampsia risk in autologous frozen embryo transfer in natural vs artificial cycles. Impaired endometrial function because of suboptimal hormonal administration is an alternative but not mutually exclusive explanation for increased preeclampsia risk in autologous frozen embryo transfer in artificial cycles. Potential mechanisms by which the corpus luteum may reduce the risk of developing preeclampsia and whether autologous frozen embryo transfer in artificial cycles is associated with increased risk of preterm preeclampsia, term preeclampsia, or both are discussed. Last, suggestions for future investigations are noted.

Right Ventricular Dyssynchrony in Patients With Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC. CONCLUSIONS: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

Insulin stimulation reduces aortic wave reflection in adults with metabolic syndrome.

Adults with metabolic syndrome (MetS) have increased fasting arterial stiffness and altered central hemodynamics that contribute, partly, to increased cardiovascular disease (CVD) risk. Although insulin affects aortic wave reflections in healthy adults, the effects in individuals with MetS are unclear. We hypothesized that insulin stimulation would reduce measures of pressure waveforms and hemodynamics in people with MetS. Thirty-five adults with obesity (27 women; 54.2 ± 6.0 yr; 37.1 ± 4.8 kg/m2) were selected for MetS (ATP III criteria) following an overnight fast. Pulse wave analysis was assessed using applanation tonometry before and after a 2-h euglycemic-hyperinsulinemic clamp (90 mg/dL, 40 mU/m2/min). Deconvolution analysis was used to decompose the aortic waveform [augmentation index corrected to heart rate of 75 beats/min (AIx@75); augmentation pressure (AP)] into backward and forward pressure components. Aerobic fitness (V̇o2max), body composition (DXA), and blood biochemistries were also assessed. Insulin significantly reduced augmentation index (AIx@75, 28.0 ± 9.6 vs. 23.0 ± 9.9%, P < 0.01), augmentation pressure (14.8 ± 6.4 vs. 12.0 ± 5.7 mmHg, P < 0.01), pulse pressure amplification (1.26 ± 0.01 vs. 0.03 ± 0.01, P = 0.01), and inflammation [high-sensitivity C-reactive protein (hsCRP): P = 0.02; matrix metallopeptidase 7 (MMP-7): P = 0.03] compared to fasting. In subgroup analyses to understand HTN influence, there were no insulin stimulation differences on any outcome. V̇o2max, visceral fat, and blood potassium correlated with fasting AIx@75 (r = -0.39, P = 0.02; r = 0.41, P = 0.03; r = -0.53, P = 0.002). Potassium levels were also associated with insulin-mediated reductions in AP (r = 0.52, P = 0.002). Our results suggest insulin stimulation improves indices of aortic reflection in adults with MetS.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on central and peripheral hemodynamics in adults with metabolic syndrome. We provide evidence that insulin infusion reduces aortic wave reflection, potentially through a reduction in inflammation and/or via a potassium-mediated vascular response.

The Differential Impact of the Left Atrial Pressure Components on Pulmonary Arterial Compliance-Resistance Relationship in Heart Failure.

BACKGROUND: An increase in the pulmonary capillary wedge pressure (PAWP) has been shown to impact on the inherent relationship between the pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR), thus augmenting the pulsatile relative to the resistive load of the right ventricle. However, the PAWP comprises the integration of both the steady and the pulsatile pressure components. We sought to address the differential impact of the these distinct PAWP components on the PAC-PVR relationship in a cohort of patients with heart failure. METHODS AND RESULTS: The study population consisted of 192 patients with hemodynamic findings diagnostic for heart failure. Off-line analysis was performed using the MATLAB software. The steady and pulsatile PAWP components were calculated as mid-A pressure and mean pressure during the V-wave oscillation, respectively. The PAC and PVR were hyperbolically and inversely associated and the subgroup of patients with PAWP above the median (>18 mm Hg) displayed a significant left and downward shift of the curve fit (P < .001). The shift in the PAC-PVR fit between patients with higher versus low steady PAWP was not significant (P = .43). In contrast, there was a significant downward and leftward shift of the PVR-PAC curve fit for the subgroup with a higher pulsatile PAWP (P < .001). Furthermore, only the pulsatile PAWP was significantly associated with the time-constant of the pulmonary circulation, assessed as the PAC × PVR product (P < .001). CONCLUSIONS: In patients with heart failure, the pulsatile rather than the steady PAWP component stands for the previously documented shift of the PAC-PVR relationship occurring at an elevated PAWP.

Longitudinal association between leisure-time physical activity and vascular elasticity indices.

AIM: We investigated the association between levels of leisure-time physical activity and vascular stiffness in a longitudinal observational study from a representative Swedish population. METHOD: A total of 2816 randomly selected individuals were examined at visit 1 (2002-2005, Men = 1400). After a mean follow-up of 9.7 ± 1.4 years, a representative sample of 1327 of the original participants were re-examined at visit 2. After excluding subjects with hypertension at baseline, 761 participants were included in the longitudinal analyses. Leisure-time physical (LTPA) activity was self-reported and dichotomized as high or low (level 3, 4 and level 1, 2, respectively). Large Arterial Elasticity Index (LAEI) and Small Arterial Elasticity Index (SAEI) were measured using the HDI/Pulse Wave™ CR2000. Multivariable general linear models were used to investigate the differences in changes SAEI and LAEI based on LTPA levels. RESULTS: At visit 1, and after adjustment for possible confounders, participants in the high LTPA group had better small artery elasticity (SAEI) (SAEI in low-level LTPA: 7.89 ± 0.11, SAEI in high-level LTPA: 8.32 ± 0.15, ΔSAEI: 0.42, CI: 0.07-0.78; p = 0.020). SAEI decreased between the two assessments (Visit 1: SAEI 8.01 ± 3.37 ml/mmHg; Δ SAEI: 1.4, CI 1.2-1.6, p < 0.001). Participants with a higher LTPA at visit 1 had significantly better SAEI at visit 2 (ΔSAEI: 0.44, CI 0.03-0.85, p = 0.037). No significant associations were observed between LAEI and LTPA after adjustments. CONCLUSIONS: High LTPA predicted higher small arterial compliance at visit 2 suggesting that positive effects of LTPA on arterial elasticity persists over time.

Effect of Supervised Training Therapy on Pulmonary Arterial Compliance and Stroke Volume in Severe Pulmonary Arterial Hypertension and Inoperable or Persistent Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Pulmonary arterial compliance (PAC) is a prognostic parameter in pulmonary arterial hypertension (PAH) reflecting the elasticity of the pulmonary vessels. OBJECTIVES: The objective of this post hoc analysis of a prospective randomized controlled trial (RCT) was to assess the effect of exercise training on PAC and stroke volume (SV) in patients with PAH and persistent/inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHOD: From the previous RCT, 43 out of 87 patients with severe PAH (n = 29) and CTEPH (n = 14) had complete haemodynamic examinations at baseline and after 15 weeks by right heart catheterization and were analysed (53% female, 79% World Health Organization functional class III/IV, 58% combination therapy, 42% on supplemental oxygen therapy, training group n = 24, and control group n = 19). Medication remained unchanged for all patients. RESULTS: Low-dose exercise training at 4-7 days/week significantly improved PAC (training group 0.33 ± 0.65 mL/mm Hg vs. control group -0.06 ± 1.10 mL/mm Hg; mean difference 0.39 mL/mm Hg, 95% confidence interval [CI] 0.15-0.94 mL/mm Hg; p = 0.004) and SV (training group 9.9 ± 13.4 mL/min vs. control group -4.2 ± 11.0 mL/min; mean difference 14.2 mL, 95% CI 6.5-21.8 mL; p < 0.001) in the training versus control group. Furthermore, exercise training significantly improved cardiac output and pulmonary vascular resistance at rest, peak oxygen consumption, and oxygen pulse. CONCLUSIONS: Our findings suggest that supervised exercise training may improve right ventricular function and PAC at the same time. Further prospective studies are needed to evaluate these findings.

Greater arterial wall viscosity in endurance-trained men.

PURPOSE: The age-associated increase in arterial wall viscosity (AWV) is attenuated by high cardiorespiratory fitness level. However, AWV in endurance-trained athletes have not been determined. We designed a cross sectional study to compare central AWV and compliance between endurance-trained young athletes and age-matched control men. METHODS: Twenty-one endurance-trained men (age 20.7 ± 0.3 years) and 20 age-matched healthy control men (age 21.6 ± 0.4 years) were studied. The common carotid artery was measured noninvasively by tonometry and automatic tracking of B-mode images to obtain instantaneous pressure and diameter hysteresis loops, and we calculated the dynamic carotid arterial compliance, static (effective and isobaric) compliance, and viscosity index. RESULTS: The AWV index in the endurance-trained men was larger than the control peers (2285 ± 181 vs. 1429 ± 124 mmHg·s/mm: P < 0.001). In addition, dynamic and static compliance were not statistically different between both groups. CONCLUSION: The present study indicated that the central AWV in endurance-trained athletes was greater than age-matched healthy control men. We believe that the AWV, as well as arterial compliance, is an important element for assessing vascular adaptation to endurance training.

Heart Failure With Preserved Ejection Fraction: A Comprehensive Review and Update of Diagnosis, Pathophysiology, Treatment, and Perioperative Implications.

Almost three-quarters of all heart failure patients who are older than 65 have heart failure with preserved ejection fraction (HFpEF). The proportion and hospitalization rate of patients with HFpEF are increasing steadily relative to patients in whom heart failure occurs as result of reduced ejection fraction. The predominance of the HFpEF phenotype most likely is explained by the prevalence of medical conditions associated with an aging population. A multitude of age-related, medical, and lifestyle risk factors for HFpEF have been identified as potential causes for the sustained low-grade proinflammatory state that accelerates disease progression. Profound left ventricular (LV) systolic and diastolic stiffening, elevated LV filling pressures, reduced arterial compliance, left atrial hypertension, pulmonary venous congestion, and microvascular dysfunction characterize HFpEF, but pulmonary arterial hypertension, right ventricular dilation and dysfunction, and atrial fibrillation also frequently occur. These cardiovascular features make patients with HFpEF exquisitely sensitive to the development of hypotension in response to acute declines in LV preload or afterload that may occur during or after surgery. With the exception of symptom mitigation, lifestyle modifications, and rigorous control of comorbid conditions, few long-term treatment options exist for these unfortunate individuals. Patients with HFpEF present for surgery on a regular basis, and anesthesiologists need to be familiar with this heterogeneous and complex clinical syndrome to provide successful care. In this article, the authors review the diagnosis, pathophysiology, and treatment of HFpEF and also discuss its perioperative implications.

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

BACKGROUND: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. METHODS: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. RESULTS: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. CONCLUSIONS: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Australian Clinical Trials Registry, ACTRN12610000650099.

Invasive Hemodynamics in Heart Failure with Preserved Ejection Fraction: Importance of Detecting Pulmonary Vascular Remodeling and Right Heart Function.

Heart failure (HF) is an ongoing crisis reaching epidemic proportions worldwide. About 50% of HF patients have a preserved ejection fraction. Invasive hemodynamics have shown varied results in patients who have HF with preserved ejection fraction (HFpEF). This article attempts to summarize the importance of detecting pulmonary vascular remodeling in HFpEF using invasive hemodynamics. Incorporating newer invasive hemodynamic parameters such as diastolic pulmonary gradient, pulmonary arterial compliance, pulmonary vascular resistance, and pulmonary arterial pulsatility index may improve patient selection for studies used in defining advanced therapies and clinical outcomes. Profiling of patients using invasive hemodynamic parameters may lead to better patient selection for clinical research.

Effect of Half-Marathon Running on Arterial Stiffness and Blood Biomarkers in High-Level and Recreational Male Athletes.

There is no clear understanding about the effect of intensive physical load on arterial stiffness and related biomarkers. The aim of this study was to evaluate the effect of half-marathon running on arterial stiffness and blood biomarkers during post-competitive recovery period in competitive and recreational male athletes. Eleven high-level long-distance runners (27.1 ± 4.8 yrs) and seven recreational athletes (34.3 ± 6.1 yrs), who participated in a half-marathon run were examined. Blood biomarkers and arterial stiffness (SphygmoCor 7.1) were measured at baseline and at 18 to 22 hours after the competition. There were no statistically significant changes between the groups in augmentation index (AIx, AIx@75) or pulse wave velocities at carotid-femoral segment (cfPWV) during recovery period. Between-group comparison did not reveal significant differences in blood pressure and arterial stiffness values at baseline and during recovery period. The change of cfPWV (difference between cfPWV at baseline and cfPWV during post-competitive recovery period) was significantly dependent on race time and sports level of the athlete (high-level or recreational). A significant increase was found in hsCRP, creatine kinase and LDH activity during the post-race period in both groups. No significant changes were found in oxidative stress markers in the groups after the race except for higher diene conjugates level in recreational athletes in comparison with the high-level group during recovery period. Our study results showed that half-marathon competition did not cause any significant changes in arterial stiffness parameters during the recovery period. However, the change in cfPWV was independently associated with half-marathon race time and the athlete's level of training revealing a mild increase of arterial stiffness in high-level athletes and athletes with a faster race time.

Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial.

Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b-4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m2 and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1-202) pg/mL and 221.1 (154.3-334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63-5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.