Determinants of elevated carbohydrate antigen 125 in patients with severe symptomatic aortic valve stenosis referred for transcatheter aortic valve implantation

Purpose: Elevated carbohydrate antigen 125 (CA125) predicts adverse outcome after transcatheter aortic valve implantation (TAVI). While known underlying pathophysiological mechanisms of elevated CA125 include serosal effusions and inflammatory stimuli, clinical determinants associated with elevated CA125 in patients referred for TAVI remain unknown. Therefore, we investigated clinical, laboratory and echocardiographic determinants of elevated CA125 in patients with severe aortic valve stenosis referred for TAVI.

Methods: This study includes 650 patients with severe aortic stenosis referred for TAVI. Baseline CA125 was determined by an immunoassay and dichotomized (elevated versus normal) based on the manufacturer cutoff value (>35?U/mL).

Results: CA125 elevation was present in 28% (181/650). Patients with elevated CA125 had an overall worse clinical profile and were more symptomatic with a higher rate of NYHA class III/IV (80% versus 58%; p?Conclusion: Elevated CA125 levels in patients referred for TAVI summarize a subset of patients with an overall worse clinical profile who are more symptomatic.     

Timing of cardiac contraction in humans mapped by high-temporal-resolution MRI tagging: early onset and late peak of shortening in lateral wall

Mechanical asynchrony is an important parameter in predicting the response to cardiac resynchronization therapy, but detailed knowledge of cardiac contraction timing in healthy persons is scarce. In this work, timing of cardiac contraction was mapped in 17 healthy subjects with high-temporal-resolution (14 ms) MRI myocardial tagging and strain analysis. Both the onset time of circumferential shortening (T(onset)) in early systole and the time of peak circumferential shortening (T(peak)) at end systole were determined. The onset of shortening width (time needed for 20-90% of the left ventricle to start shortening) was small (35 +/- 9 ms). A distinct spatial pattern for T(onset) was found, with earliest onset in the lateral wall and latest onset in the septum (P = 0.001). Compared with T(onset), T(peak) had a larger width (121 +/- 22 ms) and an opposite spatial pattern, with peak shortening occurring earlier in the septum than in the lateral wall (P < 0.001). Postsystolic shortening (T(peak) later than aortic valve closure; P < 0.05) was observed in 13 of the 30 cardiac segments, mainly in the lateral and basal segments. Shortening in these segments continued 58 +/- 14 ms after aortic valve closure, during which circumferential shortening increased from 16.9 +/- 1.2% to 20.0 +/- 1.5%. Maps of the timing of contraction in normal subjects may serve as a reference in detecting mechanical asynchrony due to intraventricular conduction defects or ischemia.     

The effect of aortic valve replacement on quality of life in symptomatic patients with severe aortic stenosis

Background

Although symptomatic patients with severe aortic stenosis have a high disease burden and guidelines recommend aortic valve replacement, many are treated conservatively. This study describes to what extent quality of life is changed by aortic valve replacement relative to conservative treatment.

Methods

This observational study followed 132 symptomatic patients with severe aortic stenosis who were subjected to an SF-36v2TM Health Survey.

Results

At baseline 84 patients were treated conservatively, 48 were referred for aortic valve replacement. In the conservatively treated group 15 patients died during a mean follow-up of 18 months (Kaplan-Meier survival was 85 % and 72 % at one and 2 years respectively) and 22 patients crossed over to the surgical group. Of the resulting 70 patients in the surgical group 3 patients died during a mean follow-up of 11 months (survival 95 % at 1 year). Physical functioning, vitality and general health improved significantly 1 year after aortic valve replacement. In conservatively treated patients physical quality of life deteriorated over time while general health, vitality and social functioning showed a declining trend. Mental health remained stable in both groups.

Conclusions

Aortic valve replacement improves physical quality of life, general health and vitality in patients with symptomatic severe aortic stenosis. Besides having a low life expectancy, conservatively treated patients experience deterioration of physical quality of life. Health surveys such as the SF-36v2TM can be valuable tools in monitoring the burden of disease for an individual patient and offer additional help in treatment decisions.     

The relationships of phytosterols and oxyphytosterols in plasma and aortic valve cusps in patients with severe aortic stenosis

Phytosterols such as campesterol and sitosterol are susceptible to oxidation by reactive oxygen species. We hypothesize that the plant sterols (PS) campesterol and sitosterol and their 7-oxygenated metabolites (POPs) correlate within and between human plasma and aortic valve cusps tissues. Plasma and tissue concentrations of PS and POPs were analyzed by gas chromatography–mass spectrometry-selected ion monitoring. Prior to analysis valve cusps tissue was mechanically separated from the calcified parts. PS and POP levels per dry cusps tissue weight were significantly higher compared with the concentrations in the calcified part. Against our hypothesis we found that despite the fact that there is a high correlation between plant sterols in and between plasma and valves cusps tissue, as well as a high correlation between plant sterols and oxyphytosterols and oxyphytosterols themselves within the valve cusps tissue, there was hardly any correlation in the amount of oxyphytosterols in plasma and between plasma and valves. Because plasma samples are easily accessible for large scale population based studies, we have to understand in more detail what the analysis of POPs implies in terms of CVD risk for the future.     

Balloon dilatation of the aortic valve for inoperable aortic stenosis.

The place of balloon dilatation of the aortic valve in the treatment of calcific aortic stenosis is controversial. Thirty two patients (mean age 76) in whom valve replacement was contraindicated were followed up for three to 24 months (mean 8); 25 were in functional class III or IV according to the New York Heart Association''s classification. Major complications of the procedure occurred in four patients. Echocardiography and Doppler studies were performed before operation and before discharge in 28 patients, and the area of the valve was measured again six to 50 (mean 23) weeks after operation in 11 patients. The peak to peak aortic pressure gradient fell from a mean of 65 (SD 24) to 46 (20) mm Hg, but the area of the aortic valve, measured by Doppler echocardiography, in 18 patients showed a modest but significant increase, from 0.61 (0.16) to 0.74 (0.23) cm2. One month after dilatation, 29 patients were alive, of whom 17 had improved symptoms. Only two had lasting clinical benefit. Sixteen patients died, 12 of a cardiac cause. The estimated one year survival rate was 49%. Six patients underwent or required valve replacement because of persisting symptoms. In view of its limited long term efficacy balloon dilatation of the aortic valve should be used only for patients with severe symptoms whose life expectancy is limited by other disease or who are considered to be unsuitable for valve replacement. It may have a role in improving the condition of patients who present with cardiogenic shock or pulmonary oedema before valve replacement is undertaken.     

Angiogenic activation of valvular endothelial cells in aortic valve stenosis

Here, we demonstrate the angiogenic response of valvular endothelial cells to aortic valve (AV) stenosis using a new ex vivo model of aortic leaflets. Histological analysis revealed neovascularization within the cusps of stenotic but not of non-stenotic aortic valves. Correspondingly, the number of capillary-like outgrowth in 3D collagen gel was significantly higher in stenotic than in non-stenotic valves. Capillary-like sprouting was developed significantly faster in stenotic than in non-stenotic valves. New capillary sprouts from stenotic aortic valves exhibited the endothelial cell markers CD31, CD34 and von-Willebrand factor (vWF) as well as carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1), Tie-2 and angiogenesis inhibitor endostatin. Western blot analyses revealed a significant increase of CEACAM1 and endostatin in stenotic aortic valve tissue. Electron microscopic examinations demonstrate that these capillary-like tubes are formed by endothelial cells containing Weibel-Palade bodies. Remarkably, inter-endothelial junctions are established and basement membrane material is partially deposited on the basal side of the endothelial tubes. Our data demonstrate the capillary-like sprout formation from aortic valves and suggest a role of angiogenesis in the pathogenesis of aortic valve stenosis. These data provide new insights into the mechanisms of valvular disorders and open new perspectives for prevention and early treatment of calcified aortic stenosis.     

The role of cardiac biochemical markers in aortic stenosis

Calcified aortic stenosis is one of the most common causes of heart failure in the elderly. Current guidelines recommend aortic valve replacement in patients with severe disease and evidence of decompensation based on either symptoms or impaired systolic ejection fraction. However, symptoms are often subjective whilst impaired ejection fraction is not a sensitive marker of ventricular decompensation. Interest has surrounded the use of cardiac biochemical markers as objective measures of left ventricular decompensation in aortic stenosis. We will first examine mechanisms of release of biochemical markers associated with myocardial wall stress (BNP/NT-proBNP), myocardial fibrosis (markers of collagen metabolism, galectin-3, soluble ST2) and myocyte death/myocardial ischemia (high-sensitivity cardiac troponins, heart-type fatty acid binding protein, myosin-binding protein C); and discuss future directions of these markers.     

Tryptase as a marker of severity of aortic valve stenosis

Background

Severe aortic valve stenosis is one of the most common cause of mortality in adult patients affected with metabolic syndrome, a condition associated with an active inflammatory process involving also mast cells and their mediators, in particular tryptase. The aim of this study was to characterize the possible long-term prognostic role of tryptase in severe aortic valve stenosis.

Case presentation

The baseline serum tryptase was measured in 5 consecutive patients admitted to our Hospital to undergo aortic valve replacement for severe acquired stenosis. Within 2 years after, the patients were evaluated for the occurrence of major cardiovascular events (MACE). The tryptase measurements were higher in patients experiencing MACE (10.9, 11.7 and 9.32 ng/ml) than in non-MACE ones (5.69 and 5.58 ng/ml).

Conclusions

In patients affected with severe aortic stenosis, baseline serum tryptase may predict occurence of MACE. Further studies are needed to demonstrate the long-term prognostic role of this biomarker.

     

Transmural gradients of oxygen tension on cerebral microvessels in rats

Using modified oxygen needle microelectrodes, vital microscopy with video-recording facilities, measurements of tissue oxygen tension (PO2) profiles near the cortical arterioles and transmural PO2 gradients on pial arterioles of the rat were performed. At control transmural PO2 gradient averaged 1.17 +/- 0.06 mm Hg/microm (mean +/- SEM, n = 40). Local dilatation of the arteriolar wall (microapplication of sodium nitroprusside approximately 2 x 10(-7) M) resulted in marked drop of the transmural PO2 gradient to 0.68 +/- 0.04 mm Hg/microm (p < 0.001, n = 38). The important finding of the study is the dependence of the transmural PO2 gradient on the vascular tone of pial arterioles. The data presented allow to conclude that O2 consumption of the arteriolar wall lies within the range for surrounding tissue and O2 consumption of the endothelial layer and, apparently, has no substantial impact on transmural PO2 gradient.     

Impaired subendocardial contractile myofiber function in asymptomatic aged humans, as detected using MRI

With aging, structural and functional changes occur in the myocardium without obvious impairment of systolic left ventricular (LV) function. Transmural differences in myocardial vulnerability for these changes may result in increase of transmural inhomogeneity in contractile myofiber function. Subendocardial fibrosis and impairment of subendocardial perfusion due to hypertension might change the transmural distribution of contractile myofiber function. The ratio of LV torsion to endocardial circumferential shortening (torsion-to-shortening ratio; TSR) during systole reflects the transmural distribution of contractile myofiber function. We investigated whether the transmural distribution of systolic contractile myofiber function changes with age. Magnetic resonance tissue tagging was performed to derive LV torsion and endocardial circumferential shortening. TSR was quantified in asymptomatic young [age 23.2 (SD 2.6) yr, n = 15] and aged volunteers [age 68.8 (SD 4.4) yr, n = 16]. TSR and its standard deviation were significantly elevated in the aged group [0.47 (SD 0.12) aged vs. 0.34 (SD 0.05) young; P = 0.0004]. In the aged group, blood pressure and the ratio of LV wall mass to end-diastolic volume were mildly elevated but could not be correlated to the increase in TSR. There were no significant differences in other indexes of systolic LV function such as end-systolic volume and ejection fraction. The elevated systolic TSR in the asymptomatic aged subjects suggests that aging is associated with local loss of contractile myofiber function in the subendocardium relative to the subepicardium potentially caused by subclinical pathological incidents.     

Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis

AimsEndocannabinoids and their receptors have been associated with cardiac adaptation to injury, inflammation and fibrosis. Experimental studies suggested a role for inflammatory reaction and active remodeling in myocardial hypertrophy, but they have not been shown in human hypertrophy. We investigated the association of the endocannabinoid system with myocardial hypertrophy in patients with aortic stenosis.Main methodsMyocardial biopsies were collected from patients with aortic stenosis (AS) and atrial myxoma as controls during surgery. Histological and molecular analysis of endocannabinoids and their receptors, inflammatory and remodeling-related cells and mediators was performed.Key findingsMyocardial hypertrophy was confirmed with significantly higher cardiomyocyte diameter in AS than in myxoma patients, which had normal cell size. AS patients presented compensated myocardial adaptation to pressure overload. AS patients had significantly higher: concentration of endocannabinoid anandamide, expression of its degrading enzyme FAAH, and of cannabinoid receptor CB2, being predominantly located on cardiomyocytes. Cell density of macrophages and newly recruited leukocytes were higher in AS group, which together with increased expression of chemokines CCL2, CCL4 and CXCL8, and suppression of anti-inflammatory IL-10 indicates persistent inflammatory reaction. We found higher myofibroblast density and stronger tenascin C staining along with mRNA induction of tenascin C and CTGF in AS patients showing active myocardial remodeling.SignificanceOur study shows for the first time activation of the endocannabinoid system and predominant expression of its receptor CB2 on cardiomyocytes being associated with persistent inflammation and active remodeling in hypertrophic myocardium of patients with aortic stenosis.     

Balloon aortic valvuloplasty as a bridge to aortic valve replacement in a patient with severe calcific aortic stenosis

This case report describes a patient with severe calcific aortic stenosis who was initially considered inoperable because of a very poor left ventricular function and severe pulmonary hypertension. After balloon aortic valvuloplasty, the clinical and haemodynamic status of the patient improved to such an extent that subsequent aortic valve replacement was considered possible and eventually proved to be successful. Balloon aortic valvuloplasty has value as a potential bridge to aortic valve replacement when the risks for surgery are considered to be too high.     

Management of a protruding right coronary artery stent during aortic valve replacement for aortic stenosis

ABSTRACT: We describe the successful management of a stent protruding from the right coronary ostium into the aortic root in the setting of aortic valve replacement for aortic stenosis. Due to advances in medical care more elderly patients present for aortic valve surgery after percutaneous coronary intervention. Therefore, with an aging population due to advances in medical care, more patients will present for aortic valve surgery after percutaneous coronary intervention. We suggest a degree of caution before valve deployment in transcatheter aortic valve intervention or during annular manipulation in patients undergoing traditional aortic valve replacement with coexisting patent proximal stents.     

Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis

Calcific aortic valve stenosis is the most common indication for surgical valve replacement. Inflammation appears to be one of the mechanisms involved in aortic valve calcification, and valve interstitial cells seem to contribute to that process. Although Toll-like receptors (TLRs) play an important role in the cellular inflammatory response, it is unknown whether human aortic valve interstitial cells (HAVICs) express functional TLRs. We examined the expression of TLR2 and TLR4 in human aortic valve leaflets and in isolated HAVICs and analyzed the response of cultured HAVICs to the TLR2 and TLR4 agonists peptidoglycan (PGN) and LPS. Abundant TLR2 and TLR4 proteins were found in human aortic valve leaflets and in isolated HAVICs, and both receptors were detected in the membrane and cytoplasm of cultured HAVICs. Stimulation by either PGN or LPS resulted in the activation of the NF-kappaB signaling pathway and the production of multiple proinflammatory mediators, including IL-6, IL-8, and ICAM-1. In addition, stimulation by either PGN or LPS upregulated the expression of bone morphogenetic protein-2 (BMP-2) and Runx2, factors associated with osteogenesis. This study demonstrates for the first time that HAVICs express TLR2 and TLR4 and that stimulation of HAVICs by PGN or LPS induces the expression of proinflammatory mediators and the upregulation of osteogenesis-associated factors. These results suggest that TLR2 and TLR4 may play a role in aortic valve inflammation and stenosis.