Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and NO consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb and plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05603520. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01805739.

Cocoa flavanols improve peakVO2 and exercise capacity in a randomized double blinded clinical trial in healthy elderly people.

Background: Loss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity. Aim: To investigate the effect of CF on cardiorespiratory-fitness in healthy elderly people. Methods: In a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly people (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2 per heart rate (HR)), resting blood pressure (BP), and resting vascular function. Results: After 30 days of CF intake peakVO2 increased by 190 ml min-1 (95% CI 1-371 ml min-1) and peakVO2 per kg by 2.5 ml (min kg)-1 (95% CI 0.30-4.2 ml (min kg)-1). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 to -0.1 mmHg) and 2.9 mmHg (95% CI -5.5 to -0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79%) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control. Conclusion: CF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Cocoa flavanol supplementation preserves early and late radial artery function after transradial catheterization.

Background: The transradial approach for coronary angiography is associated with fewer complications and preferred over the femoral approach. Injury to the radial artery (RA) endothelium elicits intimal hyperplasia, possibly resulting in total occlusion and limb functional decline. Flavanols are known to improve endothelial function. Effects on arterial remodeling after mechanical injury are unknown. Objective: To investigate the effects of cocoa flavanols on (a) intimal hyperplasia and (b) endothelial functional recovery after mechanical vascular wall injury through transradial coronary angiography (TCA). Methods: Primary endpoint in this double-blind, randomized, controlled trial was RA intima-media thickness (IMT) after 6 months follow-up (FU). Secondary endpoints were RA flow-mediated vasodilation (FMD) and fractional diameter change (Fdc). Further luminal diameter and circulating endothelial microparticles (EMP) were assessed. Thirty-six male patients undergoing elective TCA were included. Flavanol or matched placebo supplementation started 7 days prior TCA (cocoa flavanol 1000 mg day-1) for 14 days. Four measurements spanned three periods over 6-moths-FU. Results: TCA induced sustained intimal hyperplasia in the placebo-, but not in the flavanol-group (IMT 0.44 ± 0.01 vs. 0.37 ± 0.01 mm, p = 0.01). FMD decreased after TCA in both groups, but recovered to baseline after 6 months in the flavanol group only. Fdc acutely decreased, EMPs increased in the placebo-, not in the flavanol -group. Luminal diameter remained unchanged in both groups. Conclusion: Peri-interventional cocoa flavanol supplementation prevents long-term intima media thickening and endothelial dysfunction 6 months after TCA opening the perspective for dietary interventions to mitigate endothelial cell damage and intimal hyperplasia after mechanical injury.

Elevated Initial Serum Phosphate Levels Predict Higher Mortality and Impaired Neurological Outcome in Cardiac Arrest Patients with Return of Spontaneous Circulation.

Purpose: Although a moderate proportion of cardiac arrest (CA) patients achieve a return of spontaneous circulation (ROSC), few survive to discharge, mostly with poor neurological development. As serum phosphate levels were described as elevated after cardiopulmonary resuscitation (CPR), we asked whether these elevations would predict a higher risk of mortality and impaired neurological outcome in CA patients following ROSC. Methods: Initial serum phosphate levels, survival, and neurologic status at discharge of 488 non-traumatic CA patients treated at a single German hospital after achieving ROSC were analyzed. The cut-off value of phosphate for mortality prediction was determined using the receiver operator characteristic (ROC) curve, and patients were divided accordingly for comparison. Results were validated by analyzing phosphate levels in a multi-centric cohort containing 3299 CA patients from the eICU database of the United States. Results: In the German cohort, ROC analysis showed a 90% specificity for phosphate levels >2.7 mmol/L to predict mortality (AUC: 0.76, p < 0.0001), and phosphate level elevations were associated with higher in-hospital mortality (crude odds ratio 3.04, 95% CI 2.32 to 4.08). Patients with initial phosphate levels >2.7 mmol/L had significantly higher mortality in both analyzed collectives (p < 0.0001). Similarly, patients from the German cohort who initially had higher phosphate levels also showed a higher proportion of impaired neurological status at discharge and morphological signs of brain injury. Conclusions: In CA patients following ROSC, initial serum phosphate levels >2.7 mmol/L predict higher mortality and impaired neurological outcome. Our data suggests that phosphate determination might improve the preciseness of the overall and neurologic prognostication in patients after CPR following ROSC.

Thromboembolic Events in Patients With Left Ventricular Assist Devices Are Related to Microparticle-Induced Coagulation.

Thromboembolic events (TEs) are a feared complication in patients supported by a continuous-flow left ventricular assist device (LVAD). The aim of the study was to analyze the role of circulating microparticles (MPs) in activating the coagulation system in LVAD patients, which might contribute to the occurrence of TEs. First, we analyzed the effect of LVAD support on endothelial function, on the levels of endothelial MPs (EMPs) and platelet MPs (PMPs), and on the procoagulative activity of circulating MPs (measured as MP-induced thrombin formation) before LVAD implantation, post-implantation, and at a 3 month follow-up (n = 15). Second, these parameters were analyzed in 43 patients with ongoing LVAD support who were followed up for the occurrence of TEs in the following 12 months. In patients undergoing LVAD implantation, the levels of PMPs and MP-induced thrombin formation increased post-LVAD implantation. The flow-mediated vasodilation (FMD) decreased, while the levels of EMPs increased post-LVAD implantation. TEs occurred in eight patients with ongoing LVAD support despite adequate coagulation. The levels of PMPs and MP-induced thrombin formation were higher in LVAD patients with TEs than in LVAD patients without TEs and were independent predictors for the risk of TEs under LVAD support. As conclusion, implantation of LVAD enhanced MP-induced coagulation, which was independently associated with the occurrence of TEs. These parameters may serve in risk stratification for early transplantation and individualized modification of standard LVAD therapy.