Age-related atrial fibrosis.

Many age-related diseases are associated with, and may be promoted by, cardiac fibrosis. Transforming growth factor (TGF)-beta, hypoxia-induced factor (HIF), and the matrix metalloproteinase (MMP) system have been implicated in fibrogenesis. Thus, we investigated whether age is related to these systems and to atrial fibrosis. Right atrial appendages (RAA) obtained during heart surgery (n = 115) were grouped according to patients' age (<50 years, 51-60 years, 61-70 years, or >70 years). Echocardiographic ejection fractions (EF) and fibrosis using Sirius-red-stained histological sections were determined. TGF-beta was determined by quantitative RT-PCR and hypoxia-related factors [HIF1 alpha, the vascular endothelial growth factor (VEGF)-receptor, CD34 (a surrogate marker for microvessel density), the factor inhibiting HIF (FIH), and prolyl hydroxylase 3 (PHD 3)] were detected by immunostaining. MMP-2 and -9 activity were determined zymographically, and mRNA levels of their common tissue inhibitor TIMP-1 were determined by RT-PCR. Younger patients (<50 years) had significantly less fibrosis (10.1% +/- 4.4% vs 16.6% +/- 8.3%) than older individuals (>70 years). While HIF1 alpha, FIH, the VEGF-receptor, and CD34 were significantly elevated in the young, TGF-beta and PHD3 were suppressed in these patients. MMP-2 and -9 activity was found to be higher while TIMP-1 levels were lower in older patients. Statistical analysis proved age to be the only factor influencing fibrogenesis. With increasing age, RAAs develop significantly more fibrosis. An increase of fibrotic and decrease of hypoxic signalling and microvessel density, coupled with differential expression of MMPs and TIMP-1 favouring fibrosis may have helped promote atrial fibrogenesis.

Imaging of the coronary venous system: validation of three-dimensional rotational venous angiography against dual-source computed tomography.

Information on the anatomy of the cardiac venous system (CVS) is increasingly important for cardiac resynchronization therapy or percutaneous transvenous mitral valve annuloplasty. Three-dimensional (3D) imaging can further improve the understanding of the relationship of cardiac structures. This study was performed to validate the accuracy of rotational coronary sinus angiography (CSA) displaying the 3D anatomy of the CVS compared to ECG-gated, contrast-enhanced, cardiac dual-source computed tomography (DSCT). Five domestic pigs (60 kg) underwent DSCT using a standardized examination protocol. Using a standard C-arm for fluoroscopy, a rotational CSA was obtained and 3D-image reconstructions performed. Side branches were identified using both methods and enumerated. Vessel visibility was estimated for each side branch and great cardiac vein/anterior interventricular vein. Also, vessel diameters were measured at distinct landmarks, i.e., side branching. The amount of contrast medium was determined and the effective radiation exposure of both methods was calculated. There was no significant difference regarding the vessel diameter of the great cardiac vein/anterior interventricular vein or its side branches. Also, estimation of vessel visibility was not different between the two imaging modalities. Estimated radiation exposure and amount of contrast medium were lower for rotational CSA. In conclusion, a 3D reconstruction of rotational CSA images is possible. All parts of the CVS are well depicted, allowing a 3D overview of the CVS anatomy. On-site 3D visualization might improve decision making during cardiac interventions. In contrast to DSCT, rotational CSA does not demonstrate the anatomy of the mitral annulus or the course of the left circumflex artery.

Pharmacological evidence for altered src kinase regulation of I (Ca,L) in patients with chronic atrial fibrillation.

A reduction in L-type Ca(2+) current (I (Ca,L)) contributes to electrical remodeling in chronic atrial fibrillation (AF). Whether the decrease in I (Ca,L) is solely due to a reduction in channel proteins remains controversial. Protein tyrosine kinases (PTK) have been described as potent modulators of I (Ca,L) in cardiomyocytes. We studied alpha(1C) L-type Ca(2+) channel subunit expression and the regulation of I (Ca,L) by PTK in chronic AF using PTK inhibitors: genistein, a nonselective inhibitor of PTK, and 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo-3,4-d-pyrimidine (PP1), a selective inhibitor of src kinases. Furthermore, type-1 and type-2A protein phosphatase activity was measured with phosphorylase as substrate in whole-cell lysates derived from atrial tissue of AF patients. Right atrial appendages were obtained from patients undergoing open-heart surgery. Protein levels of alpha(1C) L-type Ca(2+) channel subunit were determined using Western blot analysis and normalized to the protein amounts of calsequestrin as internal control. The protein concentrations of alpha(1C) did not differ between AF and sinus rhythm (SR; alpha(1C)/calsequestrin: 1.0 +/- 0.1 and 1.2 +/- 0.2, respectively, n = 8 patients). In cardiomyocytes from patients in SR (n = 20 patients), genistein and PP1 both evoked similar increases in I (Ca,L) from 3.0 +/- 0.3 to 6.1 +/- 0.8 pA/pF and from 2.8 +/- 0.4 to 6.1 +/- 0.6 pA/pF, respectively. In cells from AF patients (n = 10 patients), basal I (Ca,L) was significantly lower. In this case, genistein lead to the same relative increase in I (Ca,L) as in SR cells (from 1.46 +/- 0.30 to 3.2 +/- 1.0 pA/pF), whereas no increase was elicited by PP1 suggesting impaired regulation of I (Ca,L) by src kinases in AF. Total and type 1 and type 2A-related phosphatase activities were higher in tissue from patients with chronic AF compared to SR (4.8 +/- 0.4, 2.1 +/- 0.2, and 2.7 +/- 0.4 nmol/mg/min and 3.6 +/- 0.4, 1.3 +/- 0.2, and 2.4 +/- 0.3 nmol/mg/min, respectively, n = 7 patients per group). Downregulation of I (Ca,L) in AF is not due to a reduction in L-type Ca(2+) channel protein expression. Indirect evidence for an impaired src kinase regulation of I (Ca,L) together with an increased phosphatase activity suggests that a complex alteration in the kinase/phosphatase balance leads to I (Ca,L) dysregulation in chronic AF.

Imaging of the coronary venous system: retrograde coronary sinus angiography versus venous phase coronary angiograms.

BACKGROUND: Left ventricular lead implantation for cardiac resynchronization therapy (CRT) usually requires a pre- or intraprocedural occlusion contrast venography of the coronary sinus (CS) in order to identify tributaries to the lateral wall. As many patients undergo a preprocedural coronary angiogram, we investigated the diagnostic accuracy of venous phase imaging of the CS in patients prior to CRT implantation. The aim of this study was to assess the quality of venous phase coronary sinus angiography. METHODS: In 24 CRT patients retrograde occlusion venography and venous phase coronary sinus angiography obtained during coronary angiography were compared with respect to image quality, vessel diameters and the ability to identify a coronary sinus side branch suitable for left ventricular lead placement. RESULTS: Suitable target vessels for left ventricular lead implantation were identified in all patients irrespective of the method (retrograde occlusion venography or venous phase coronary sinus angiography). There was a high concordance in vessel diameters between venous phase and retrograde angiography. Visibility was superior in retrograde venography. CONCLUSIONS: In heart failure patients who are scheduled for coronary angiograms venous phase coronary sinus angiography is a time-saving and easy to perform alternative imaging modality. Radiation exposure and the amount of contrast medium needed is reduced as compared to coronary sinus occlusion angiography. The information obtained thereby may be used to plan subsequent CRT implantation without the need for retrograde coronary sinus angiography.

The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation.

OBJECTIVE: Electrical remodeling as well as atrial contractile dysfunction after the conversion of atrial fibrillation (AF) to sinus rhythm (SR) are mainly caused by a reduction of the inward L-type Ca(2+) current (I(CaL)). We investigated whether the expression of L-type Ca2+-channel subunits was reduced in atrial myocardium of AF patients. METHODS: Right atrial appendages were obtained from patients undergoing coronary artery bypass graft surgery (CAD, n = 35) or mitral valve surgery (MVD, n = 37). Seventeen of the CAD patients and 18 of the MVD patients were in chronic (>3 months) AF, whereas the others were in SR. The protein expression of the L-type Ca2+-channel subunits alpha1C and beta2 was quantified by western blot analysis. Furthermore, we measured the density of dihydropyridine (DHP)-binding sites of the L-type Ca2+ channel using 3H-PN220-100 as radioligand. RESULTS: Surprisingly, the alpha1C and the beta2-subunit expression was not altered in atrial myocardium of AF patients. Also, the DHP-binding site density was unchanged. CONCLUSION: The protein expression of the L-type Ca2+-channel subunits alpha1C or beta2 is not reduced in atrial myocardium of AF patients. Therefore, the reduced I(CaL) might be due to downregulation of other accessory subunits (alpha2delta), expression of aberrant subunits, changes in channel trafficking or alterations in channel function.