Heikki Turto

Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Objective—To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves. Methods and Results—Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (P<0.05 for each) and a higher total cathepsin activity (P<0.001). In stenotic valves, cystatin C mRNA was increased (P<0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system. Conclusions—Stenotic aortic valves show increased expression and activity of elastolytic cathepsins S, K, and V. These cathepsins may accelerate the destruction of aortic valvular extracellular matrix, so promoting the progression of aortic stenosis.

Exclusion of coronary artery disease by exercise thallium-201 tomography in patients with aortic valve stenosis.

In many patients with valvular aortic stenosis (AS), management decisions may be possible without invasive studies if coexistent coronary artery disease (CAD) can be ruled out noninvasively. The use of thallium-201 single-photon emission computed tomography to the exclusion of CAD was studied in 44 patients aged 41 to 78 years with AS. In addition to cardiac catheterization and selective coronary angiography, patients underwent a cardiac ultrasound study and thallium-201 myocardial perfusion imaging at rest and after bicycle ergometer exercise. Two thirds of the patients had critical AS (valve area index less than or equal to 0.5 cm2/m2) but none had left ventricular systolic dysfunction. Twenty-one patients had angiographically significant CAD (greater than or equal to 50% diameter stenosis in greater than or equal to 1 coronary artery), whereas 23 had either a fully normal angiogram (n = 17) or mild (less than 50%) stenoses (n = 6). Each patient with significant CAD had an abnormal thallium-201 tomogram, either a strictly segmental perfusion defect (n = 19), or a patchy nonsegmental abnormality (n = 2); however, 10 of 23 patients free of significant CAD had similar results. Thus, the sensitivity and specificity of an abnormal scintigram were 100 and 57%, respectively. If only segmental perfusion defects typical of CAD had been considered abnormal, then the sensitivity of the test would have been 90% and the specificity 70%. Patients with false abnormal scintigrams had more severe AS and more angiographically nonsignificant CAD than those with true normal findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload.

Osteoprotegerin (OPG) and the receptor activator of nuclear factor‐kB ligand (RANKL), two cytokines regulating bone remodeling, have recently been raised as potential pathogenetic factors in cardiovascular diseases. We have studied circulating and myocardial OPG and RANKL in patients having severe aortic stenosis (AS) with or without heart failure (HF).

Is the pregnancy hormone relaxin an important player in human heart failure

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.

Assessment of aortic valve area in aortic stenosis by magnetic resonance imaging

Abstract The ultimate determinant of the clinical significance of valvular aortic stenosis (AS) is the systolic aortic valve orifice area (AVA). AVA can be quantified either at cardiac catheterization 1 or noninvasively using transthoracic Doppler echocardiography and the continuity equation. 2 For technical reasons, the Doppler interrogation is not always successful, however, and a substitute noninvasive method for AVA determination would be welcome. Ultrafast computed tomography has shown some promise in this respect, 3 and the present report describes our initial experience with the use of magnetic resonance imaging (MRI) to directly visualize and quantify the systolic aortic valve orifice.

Leakage of cardiac troponin I in aortic valve stenosis

Objective.u2002 Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations.

Transcardiac gradients of N-terminal B-type natriuretic peptide in aortic valve stenosis.

Plasma B‐type natriuretic peptide (BNP), as well as the N‐terminal part of the prohormone (Nt‐BNP), are frequently elevated in aortic valve stenosis (AS). Yet, their release from the heart into the circulation has never been directly studied in AS.

Diagnosing heart failure in aortic valve stenosis

Objective.u2002 In aortic valve stenosis (AS), heart failure (HF) omens a high risk of death and is an indication for prompt valve replacement. We studied whether its detection can be facilitated by measuring plasma N‐terminal B‐type natriuretic peptide (Nt‐BNP) or by estimating pulmonary capillary wedge pressure (PCWP) using echocardiography.

Vasoactive intestinal peptide--release from the heart and response in heart failure due to left ventricular pressure overload.

Vasoactive intestinal peptide (VIP) is a peptidergic neurotransmitter and a vasodilator with positive inotropic and chronotropic properties. Whether and how VIP contributes to the neuroendocrine response in heart failure (HF) is disputed, and there are no data on VIP in pressure overload‐induced HF.

Transcardiac gradients of circulating apelin: extraction by normal hearts vs. release by hearts failing due to pressure overload

Apelin is a newly discovered inotropic peptide tentatively linked up with the pathophysiology of heart failure (HF). To further assess the role of apelin in HF, we measured its transcardiac arteriovenous gradients in patients with left ventricular pressure overload with or without HF and in patients with structurally normal hearts. Blood samples from the aortic root and coronary sinus were drawn from 49 adult patients undergoing preoperative cardiac catheterization for severe aortic valve stenosis (AS). Similar samples were taken from 12 control patients with structurally normal hearts undergoing electrophysiological studies. Plasma apelin was determined by enzyme immunoassay. In the control group, apelin decreased from a median of 0.39 (0.16-1.94) ng/ml in the aortic root to 0.18 (0.13-1.04) ng/ml in the coronary sinus (P = 0.004). In AS patients free of HF (n = 33), apelin concentration remained unaltered across the heart, but in those with HF (n = 15) apelin rose from a median of 0.26 (0.20-0.82) ng/ml in the aorta to 0.45 (0.24-1.17) ng/ml in the coronary sinus (P = 0.002). The transcardiac apelin gradients differed statistically highly significantly across the three groups (P = 0.00005), and each of the two-group differences was also statistically significant (P < 0.05). In conclusion, left ventricular pressure overload changes the transcardiac arteriovenous differences of circulating apelin. Although normal hearts extract apelin from the coronary blood, hearts failing due to left ventricular pressure overload release apelin into the circulation. Loss of cardiac apelin may be involved in the mechanisms of HF development in AS.