endothelin-1 and Aortic-Valve-Stenosis

Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Lipocalin-2; Male; Matrix Metalloproteinase 9; Prospective Studies; Tenascin; Tissue Inhibitor of Metalloproteinase-1; Transcatheter Aortic Valve Replacement; Vascular Remodeling

Aortic valve stenosis (AS) is an actively regulated pathobiological process which has an inflammation origin, and manifests as an accumulation of lipids and, ultimately, calcification of the aortic valve tissue. Increased plasma levels of the proinflammatory factor endothelin-1 (ET-1) have been reported in AS. Moreover, increased tissue levels of ET-1 and its ET(A) receptor, which mediates the fibrotic and proliferative effects of ET-1, have been reported in stenotic aortic valves. The study aim was to determine whether endothelin receptor antagonism has an effect on the supposed receptor-mediated uptake of ET-1 to aortic valves when ET-1 may be involved in the pathogenesis of AS.. By using valve tissue explants in culture, it was determined whether the ET(A)-ET(B) receptor antagonist tezosentan was capable of reducing the uptake of 125I-labeled ET-1 to human aortic valves. Aortic valves were obtained from 16 patients (11 males, five females; mean age 71 +/- 11.2 years) and from two donors without AS (as controls) at the time of aortic valve or aortic root surgery. Valve tissue samples were cultured in ET-1 (10 nmol/l), in the presence or absence of tezosentan (10 nmol/l).. ET-1 uptake was found to be pronounced in the calcified areas of the valve, and tezosentan markedly reduced the receptor-mediated uptake of 125I-labeled ET-1. The inhibitory effect was most evident in the well-calcified part of the valve. The gene expression levels of the ET receptors ET(A) and ET(B) were unaltered in human aortic valves during a four-day exposure to the antagonist.. The ability of the ET(A)-ET(B) receptor antagonist tezosentan to inhibit ET-1 uptake in valve tissue suggests that continuous ET antagonist therapy might serve as new strategy to slow down the pathophysiological processes of AS.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cells, Cultured; Drug Repositioning; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Pyridines; Receptor, Endothelin A; Tetrazoles; Vasodilator Agents

Due to the pathological effects of endothelin-1 (ET-1) on cardiomyocytes and the extracellular matrix, ET-1 levels may impact on the prognosis of aortic stenosis (AS) patients operated with aortic valve replacement (AVR). We examined ET-1 levels in AS patients throughout the whole AVR process, thus exposing potential therapeutic windows of opportunity.. Plasma ET-1 levels were measured before and 2 days, 6 and 12 months after AVR in 22 patients with AS. Myocardial ET-1 was measured in biopsies from 7 patients undergoing AVR. Peroperatively, plasma ET-1 was analyzed in the coronary sinus and radial artery before aortic cross-clamp and at 5 and 20 min of reperfusion, in a second group of 30 patients.. Circulating ET-1 levels were transiently increased 2.6-fold 2 days following AVR. Myocardial ET-1 protein was 2.1-fold higher in patients with AS compared to controls. Plasma levels of ET-1 correlated to echocardiographic markers of diastolic dysfunction postoperatively. There was no increase in plasma ET-1 during early reperfusion, but veno-arterial differences indicated potential cardiac ET-1 extraction.. Plasma ET-1 increases 2 days following AVR and myocardial ET-1 protein levels are increased in patients with AS before AVR. Peroperatively, no plasma ET-1 augmentation or release from the heart was observed in AS patients.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Cardiac Valve Annuloplasty; Echocardiography; Electrocardiography; Endothelin-1; Female; Humans; Immunoblotting; Male; Middle Aged; Myocardium; Prospective Studies

Endothelin-1 (ET-1) and B-type natriuretic peptide (BNP) have been reported to be involved in numerous cardiovascular diseases. The study aim was to monitor the circulating plasma levels of these peptides in patients affected by aortic disease, and to identify any changes in such levels after surgical treatment.. A total of 81 patients (52 males, 29 females; mean age 64 +/- 11 years) with aortic disease underwent surgery. The conditions included aortic valve stenosis (n=36), aortic valve regurgitation (n=11), ascending aortic aneurysm (n=6), and combined ascending aortic aneurysm and valvulopathy (n=28). Circulating plasma levels of ET-1 and BNP were measured in all patients before and at 12 months after surgery.. Compared to the preoperative situation, significant decreases were found postoperatively in plasma levels of ET-1 (4.2 +/- 0.1 versus 3.1 +/- 0.1 pM; p < 0.001) and BNP (0.071 versus 0.017 ng/ml; p < 0.001), combined with an increased cardiac function and decreased ventricular dimensions. The preoperative levels of both peptides were similar in all patient groups, and were decreased to a similar extent regardless of the diagnosis. Basal levels of ET-1 were higher in the trileaflet aortic valve compared to the bicuspid valve (4.0 +/- 0.1 versus 3.6 +/- 0.1 pM; p = 0.04).. Circulating plasma levels of ET-1 and BNP were decreased after surgery for aortic valve disease. The decrease was unrelated to the presence of ascending aortic aneurysm, and most likely represents a response to cardiac remodeling and the improved functional status of the patients.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Valve Insufficiency; Aortic Valve Stenosis; Biomarkers; Blood Vessel Prosthesis Implantation; Down-Regulation; Endothelin-1; Female; Heart Valve Prosthesis Implantation; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Recovery of Function; Stroke Volume; Sweden; Time Factors; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Aortic valve stenosis (AS) is an actively regulated process like atherosclerosis, which is accompanied by changes e.g. in endothelin-related genes. However, the role of endothelin peptides in AS is unknown.. We characterized the expression of the endothelin system in aortic valves of patients with normal valves (n = 12), regurgitation, and fibrosis (n = 6) and AS (n = 18) by reverse-transcriptase-polymerase chain reaction and immunohistochemistry. The number of endothelin-1 (ET-1) positive cells was higher in AS than in control valves, while levels of ET-1 mRNA did not differ between groups. Endothelin receptor-A (ET(A)) mRNA levels were upregulated in stenotic valves (4.3-fold, P = 0.032) associated with a remarkable increase in number of ET(A)-immunopositive cells. ET(B)-receptor mRNA levels did not change during disease progression. Endothelin-converting enzyme-1 (ECE-1) mRNA levels were 42% lower (P = 0.007) in stenotic valves. Finally, because ET-1 and ECE-1 have binding site for activator protein-1 (AP-1), we measured AP-1 DNA binding by gel shift assays, which showed significantly lower (76%, P = 0.003) activity in AS.. AS is characterized by distinct upregulation of ET-1 and its target receptor ET(A), promoting growth, inflammation, and fibrosis. These findings suggest therapeutic potential for ET(A)-receptor antagonists in aortic valve calcification.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve Stenosis; Aspartic Acid Endopeptidases; Down-Regulation; Endothelin-1; Endothelin-Converting Enzymes; Female; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; Male; Metalloendopeptidases; Middle Aged; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Receptor, Endothelin A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Inhibition of endothelin-A (ET(A)) receptors has been shown to reduce ventricular electrical abnormalities associated with cardiac failure. In this study, we investigate the effect of ET(A)-receptor inhibition on the development of regional alterations of the transient outward K(+) current (I (to)) in the setting of pressure-induced left ventricular (LV) hypertrophy. Cardiac hypertrophy was induced in female Sprague-Dawley rats by stenosis of the ascending aorta (AS) for 7 days. Treatment with the selective ET(A)-receptor antagonist darusentan (LU135252, 35 mg [kg body weight](-1) day(-1)) was started 1 day before the surgery. AS induced a 46% increase in the relative LV weight (p < 0.001) and caused a significant reduction in I (to) (at +40 mV) in epicardial myocytes (19.5 +/- 1.2 pA pF(-1), n = 32 vs 23.2 +/- 1.2 pA pF(-1), n = 35, p < 0.05). Darusentan further reduced I (to) in AS (15.4 +/- 1.3 pA pF(-1), n = 37, p < 0.05) and sham-operated animals (19.8 +/- 1.6 pA pF(-1), n = 48, ns.). The effects of AS and darusentan on I (to) were significant and independent as tested by two-way analysis of variance. I (to) was not affected in endocardial myocytes. These results indicate that endothelin-1 may exert a tonic effect on the magnitude of I (to) in the epicardial region of the left ventricle but that ET(A)-receptor activation is not necessary for the development of electrical alterations associated with pressure-induced hypertrophy.

Topics: Animals; Aortic Valve Stenosis; Blood Pressure; Disease Models, Animal; Electrophysiology; Endothelin A Receptor Antagonists; Endothelin-1; Female; Gene Expression Regulation; Heart; Hypertrophy, Left Ventricular; Myocytes, Cardiac; Phenylpropionates; Potassium; Potassium Channels; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

In aortic stenosis, natriuretic peptides have recently been shown to correlate with ventricular function and to predict symptom-free survival and outcome. Elevated big endothelin-1 (bigET) is associated with poor prognosis in chronic heart failure, but little is known about its role in severe aortic stenosis.. In 61 patients with aortic stenosis (71+/-10 years, mean gradient 65+/-20 mm Hg, valve area 0.63+/-0.15 cm2), plasma bigET was determined by radioimmunoassay and related to echocardiographic parameters, symptoms and survival. Patients were followed for 1 year.. BigET (mean 2.3+/-1.5, range 0.1-7.5 fmol/ml) was elevated > or = 1.9 fmol/ml in 54% of patients, but was not correlated to the transvalvular gradients or valve area. BigET did not differ significantly between 14 asymptomatic (2.4+/-1.0 fmol/ml) and 47 symptomatic patients (2.3+/-1.6 fmol/ml), although the highest levels were observed in 5 patients in NYHA class III-IV (4.2+/-2.2 fmol/ml, p=0.035). No significant difference in bigET was observed between 51 survivors and 10 patients who died during follow-up (2.2+/-1.4 vs 2.7+/-1.6 fmol/ml). BigET did not differ between 7 asymptomatic patients developing symptoms and those remaining asymptomatic during follow-up. BigET was significantly related to the systolic blood pressure and left ventricular systolic pressure (r=0.389, p=0.0025 and r=0.401, p=0.0018, respectively), but not to the diastolic blood pressure or interventricular septal wall thickness. BigET was inversely related to the left ventricular ejection fraction (r=0.327, p=0.01) and fractional shortening (r=0.391, p=0.044).. Although frequently elevated, bigET-1 is not a useful predictor of symptoms or outcome in patients with severe aortic stenosis. BigET increases inversely with left ventricular function and directly with systolic left ventricular and blood pressure, but is not related to transvalvular gradients or valve area.

Topics: Aged; Aortic Valve Stenosis; Biomarkers; Blood Pressure; Disease Progression; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertension; Male; Prognosis; Prospective Studies; Radioimmunoassay; Stroke Volume; Ventricular Function, Left

The pregnancy hormone relaxin has been raised as a new compensatory mediator of cardiac origin in heart failure (HF). We set out to assess the role of relaxin in pressure overload-induced human HF.. We studied 129 adult patients undergoing cardiac catheterization for isolated aortic valve stenosis (AS). Blood was sampled from the aortic root and, in a subset of 49 patients, from the coronary sinus for the determination of plasma relaxin by enzyme immunoassay. HF was diagnosed when the patient had dyspnea or fatigue on ordinary effort in association with pulmonary wedge pressure >14 mm Hg at catheterization.. Forty-one patients had HF, which was systolic (ejection fraction <50%) in 16 patients and diastolic in 25 patients. The median plasma relaxin was 32 pg/ml (<12-297 pg/ml) in 88 AS patients without HF, 28 pg/ml (<12-825 pg/ml) in the 41 AS patients with HF, and 42 pg/ml (range, <12-100 pg/ml) in 11 control patients free of heart disease (p=0.82). Plasma relaxin did not correlate with any measurement of cardiac structure or function. The concentration gradients of relaxin from the aortic root to the coronary sinus indicated relaxin extraction by the heart in the control patients (median change, -5 pg/ml, p=0.038) vs. relaxin production in patients with systolic HF (median change, +6 pg/ml, p=0.028) (p=0.002 between groups).. Although the heart may release relaxin into the circulation in certain forms of HF, this does not translate into elevated systemic concentrations. Relaxin is not a major player in human HF.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve Stenosis; Cardiac Catheterization; Cardiac Output, Low; Case-Control Studies; Endothelin-1; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Relaxin

The role of angiotensin II in pressure overload is still debated because notwithstanding its effects on myocyte contractility angiotensin II is not an obligatory factor for the development of hypertrophy. To define the role of angiotensin II in acute pressure overload we studied the effects of AT1 blockade (valsartan 80mg per day) on myocardial contractility, cardiac growth factor gene expression, and myocardial hypertrophy in aortic banded (60mmHg) pigs. Acute pressure overload caused an abrupt reduction of myocardial contractility, measured by the end-systolic stiffness constant, and a sharp increase in end-systolic stress which rapidly normalized (within 12h) in the placebo group. In AT1-blocked animals end-systolic stiffness constant remained significantly depressed up to 24h and end-systolic stress was still elevated up to 48h (both P<0.05 vs placebo). In both groups confocal microscopy revealed that granular staining of angiotensin II in cardiomyocyte cytoplasm disappeared after 30min of pressure overload. AT1 blockade abolished following cardiac overexpression of angiotensinogen and endothelin-1 genes as shown in RT-PCR studies and the consequent angiotensin II and endothelin-1 release in the coronary circulation. Conversely, insulin-like growth factor-I and ACE mRNA overexpression, as well as the onset of left ventricular mass increase, were not significantly affected by AT1 blockade.. (1) mechanical stress releases preformed angiotensin II from myocyte in vivo; (2) the AT1 blockade abolishes cardiac angiotensin II and endothelin-1 production with delayed recovery of myocardial contractility; whereas (3) the overexpression of insulin-like growth factor-I gene and the development of myocardial hypertrophy are not angiotensin II-mediated effects.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Aortic Valve Stenosis; Cardiac Catheterization; Cytoplasm; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Heart; Insulin-Like Growth Factor I; Microscopy, Confocal; Myocardium; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Stress, Mechanical; Swine; Systole; Tetrazoles; Valine; Valsartan

While the effect of neurohormones is often studied in congestive heart failure, their role in aortic stenosis needs to be elucidated.. 54 consecutive patients with symptomatic aortic stenosis without overt heart failure were studied at the age of 64.4 +/- 9.3 yrs with echocardiography, x-ray and catheterization. Levels of circulating atrial natriuretic factor endothelin-1, catecholamines, plasma renin activity, immunoreactive insulin and C-peptide were assessed, related to hemodynamic data and compared to those in 23 healthy controls, aged 59.2 +/- 12.8 yrs.. Patients had significantly higher plasma levels of endothelin-1 (z-value 0.64 +/- 1.19, p = 0.019), atrial natriuretic factor (z-value 2.46 +/- 2.46, p < 0.001) and dopamine (z-value 0.91 +/- 2.33, p = 0.02). Levels of endothelin-1 and ANF positively correlated with mean (r = 0.631, p < 0.001) and wedged pulmonary artery pressures and with left atrial diameter index (r = 0.602, p < 0.001). Endothelin-1 levels correlated negatively with aortic valve area (r = -0.306, p = 0.041). No correlation was found between neurohumoral plasma concentrations and left ventricular mass index.. In patients with symptomatic aortic stenosis without overt heart failure, elevated plasmatic levels of endothelin-1, atrial natriuretic factor and dopamine were documented. The increase of ET-1 levels is related to pulmonary hypertension and severity of the disease. Left ventricular hypertrophy is not related to neurohormonal levels. Neither circulating system renin-angiotensin nor noradrenaline are activated in these patients.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve Stenosis; Atrial Natriuretic Factor; C-Peptide; Catecholamines; Endothelin-1; Female; Humans; Insulin; Male; Middle Aged