Hans H. Sievers

Twenty-Four–Hour Holter Monitor Follow-Up Does Not Provide Accurate Heart Rhythm Status After Surgical Atrial Fibrillation Ablation Therapy: Up to 12 Months Experience With a Novel Permanently Implantable Heart Rhythm Monitor Device

Background— Twenty-four–hour Holter monitoring (24HM) is commonly used to assess cardiac rhythm after surgical therapy of atrial fibrillation (AF). However, this “snapshot” documentation leaves a considerable diagnostic window and only stores short-time cardiac rhythm episodes. To improve accuracy of rhythm surveillance after surgical ablation therapy and to compare continuous heart rhythm surveillance versus 24HM follow-up intraindividually, we evaluated a novel implantable continuous cardiac rhythm monitoring (IMD) device (Reveal XT 9525). Methods and Results— Forty-five cardiac surgical patients (male 37, mean age 69.7±9.2 years) with a mean preoperative AF duration of 38±45 m were treated with either left atrial epicardial high-intensity focus ultrasound ablation (n=33) or endocardial cryothermy (n=12) in case of concomitant mitral valve surgery. Rhythm control readings were derived simultaneously from 24HM and IMD at 3-month intervals with a total recording of 2021 hours for 24HM and 220 766 hours for IMD. Mean follow-up was 8.30±3.97 m (range 0 to 12 m). Mean postoperative AF burden (time period spent in AF) as indicated by IMD was 37±43%. Sinus rhythm was documented in 53 readings of 24HM, but in only 34 of these instances by the IMD in the time period before 24HM readings (64%, P<0.0001), reflecting a 24HM sensitivity of 0.60 and a negative predictive value of 0.64 for detecting AF recurrence. Conclusion— For “real-life” cardiac rhythm documentation, continuous heart rhythm surveillance instead of any conventional 24HM follow-up strategy is necessary. This is particularly important for further judgment of ablation techniques, devices as well as anticoagulation and antiarrhythmic therapy.

Autograft Reinforcement to Preserve Autograft Function After the Ross Procedure A Report From the German-Dutch Ross Registry

Background— Autograft reinforcement interventions (R) during the Ross procedure are intended to preserve autograft function and improve durability. The aim of this study is to evaluate this hypothesis. Methods and Results— 1335 adult patients (mean age:43.5±12.0 years) underwent a Ross procedure (subcoronary, SC, n=637; root replacement, Root, n=698). 592 patients received R of the annulus, sinotubular junction, or both. Regular clinical and echocardiographic follow-up was performed (mean:6.09±3.97, range:0.01 to 19.2 years). Longitudinal assessment of autograft function with time was performed using multilevel modeling techniques. The Root without R (Root−R) group was associated with a 6× increased reoperation rate compared to Root with R (Root+R), SC with R (SC+R), and without R (SC-R; 12.9% versus 2.3% versus 2.5%.versus 2.6%, respectively; P<0.001). SC and Root groups had similar rate of aortic regurgitation (AR) development over time. Root+R patients had no progression of AR, whereas Root−R had 6 times higher AR development compared to Root+R. In SC, R had no remarkable effect on the annual AR progression. The SC technique was associated with lower rates of autograft dilatation at all levels of the aortic root compared to the Root techniques. R did not influence autograft dilatation rates in the Root group. Conclusions— For the time period of the study surgical autograft stabilization techniques preserve autograft function and result in significantly lower reoperation rates. The nonreinforced Root was associated with significant adverse outcome. Therefore, surgical stabilization of the autograft is advisable to preserve long-term autograft function, especially in the Root Ross procedure.

Neoaortic Root Diameters and Aortic Regurgitation in Children After the Ross Operation

BACKGROUND For children who require aortic valve replacement, the Ross operation provides a unique advantage of growth potential of the pulmonary autograft in the aortic position. This study assessed the progression of autograft root diameters and its effect on aortic regurgitation (AR). METHODS Neoaortic echo dimensions from 48 children (<16 years) undergoing Ross operation who had follow-up echocardiograms before age 20 were analyzed (mean follow-up, 5.1 +/- 3.3 years). RESULTS The mean age at the time of the Ross operation was 10.0 +/- 4.3 years. Mean z values of the neoaortic annulus (1.5 +/- 0.4), sinus (2.5 +/- 0.4), and sinotubular junction (2.6 +/- 0.9) when the autograft was implanted were significantly larger compared with normal values (p < 0.001, all). The mean z values significantly increased with follow-up at the level of the sinus (0.5 +/- 0.1/year, p < 0.001) and the sinotubular junction (0.7 +/- 0.2, p < 0.001), but not at the level of the annulus (0.1 +/- 0.1, p = 0.59). AR increased with follow-up time (0.07 +/- 0.02 grade/year, p < 0.001). AR increased with sinotubular junction diameter (p = 0.028), but there was not significant evidence of an association with annulus diameter (p = 0.25) or sinus diameter (p = 0.40). CONCLUSIONS Children undergoing Ross operation have larger neoaortic root dimensions than healthy children. Growth of the annulus matches somatic growth. The diameters of the sinus and the sinotubular junction increase significantly relative to somatic growth. The latter may explain the development of AR.

Locally Different Endothelial Nitric Oxide Synthase Protein Levels in Ascending Aortic Aneurysms of Bicuspid and Tricuspid Aortic Valve

Aims. Dysregulated expression of the endothelial nitric oxide synthase (eNOS) is observed in aortic aneurysms associated with bicuspid aortic valve (BAV). We determined eNOS protein levels in various areas in ascending aortic aneurysms. Methods and Results. Aneurysmal specimens were collected from 19 patients, 14 with BAV and 5 with tricuspid aortic valve (TAV). ENOS protein levels were measured in the outer curve (convexity), the opposite side (concavity), the distal and above the sinotubular junction (proximal) aneurysm. Cultured aortic cells were treated with NO synthesis inhibitor L-NAME and the amounts of 35 apoptosis-related proteins were determined. In patients with BAV, eNOS levels were significantly lower in the proximal aorta than in the concavity and distal aorta. ENOS protein levels were also lower in the convexity than in the concavity. While the convexity and distal aorta showed similar eNOS protein levels in BAV and TAV patients, levels were higher in TAV proximal aorta. Inhibition of NO synthesis in aneurysmal aortic cells by L-NAME led to a cytosolic increase in the levels of mitochondrial serine protease HTRA2/Omi. Conclusion. ENOS protein levels were varied at different areas of the aneurysmal aorta. The dysregulation of nitric oxide can lead to an increase in proapoptotic HTRA2/Omi.

Catheter evaluation of left ventricular shape and function 1 or more years after anatomic correction of transposition of the great arteries

Twenty-eight children were reinvestigated by cardiac catheterization and angiography greater than 1 year after anatomic correction of transposition of the great arteries (TGA). Seventeen patients with simple TGA underwent banding of the pulmonary trunk plus or minus systemic to pulmonary artery shunt to prepare the left ventricle for anatomic correction. In addition to TGA, 10 of the remaining 11 patients had a large ventricular septal defect and 1 had an aorticopulmonary window. They required no preparation of the left ventricle. Age at repair ranged from 2 to 120 months (mean 26). Catheterization 12 to 48 months after anatomic repair revealed a left ventricular end-diastolic pressure of 4 to 14 mm Hg (mean 9.5 +/- 2.5 [+/- standard deviation]). Ejection fraction ranged from 52 to 75% (mean 66 +/- 8). Frame-by-frame computer-assisted analysis of left ventricular (LV) contraction and relaxation was performed in 14 patients and compared with normal left ventriculograms. Shape index, derived as 4 pi X cavity area/perimeter2 X 100, was measured in 24 patients and showed a mean index of 89 +/- 3% at end-diastole and 79 +/- 8% at end-systole. A control group had a mean diastolic index of 86 +/- 6% and mean systolic index of 73 +/- 8%. It is concluded that LV shape after anatomic correction tends to be more globular than normal and changes little during systole. LV ejection fraction and end-diastolic pressure are normal.

Influence of the two-stage anatomic correction of simple transposition of the great arteries on left ventricular function

To evaluate the influence of the 2-stage anatomic correction of simple transposition of the great arteries on left ventricular (LV) function, pressure and angiocardiographic volume data were analyzed during resting conditions shortly before banding of the pulmonary trunk (n = 12) and before (n = 17) and after anatomic correction (n = 11), and compared with data from controls (n = 12). Age at banding and anatomic correction was between 1 and 44 months (mean 16 +/- 10) and between 13 and 47 months (mean 24 +/- 10), respectively. The interval between anatomic correction and the investigation ranged from 10 to 29 months (mean 20 +/- 7). After banding, LV ejection fraction decreased (p less than 0.01) and LV peak systolic pressure (p less than 0.01) as well as LV end-diastolic pressure (p less than 0.05) increased. After anatomic correction, these variables and LV end-systolic wall stress were not significantly different from control values. The LV end-systolic wall stress-ejection fraction relation in 7 of 11 patients after anatomic correction was within control range. The highest values were found in the youngest patients at banding and at anatomic correction. In contrast to measures of global myocardial function, such as LV ejection fraction and LV end-diastolic pressure data, the LV end-systolic stress-ejection fraction relation suggest that LV function may not be normal in some patients 20 months after anatomic correction. Young age at operation, however, appears to be advantageous in preserving LV function. Hemodynamic alterations after banding probably reflect LV adaptation to systemic pressures in a hypoxemic circulation.

Inhibition of caspase-3 differentially affects vascular smooth muscle cell apoptosis in the concave versus convex aortic sites in ascending aneurysms with a bicuspid aortic valve

Apoptosis of vascular smooth muscle cells (VSMCs) is involved in bicuspid aortic valve (BAV) ascending aorta aneurysms characteristically affecting the convex site. Caspase-3 is a pivotal effector of the apoptosis machinery. The aim of this study was to investigate the impact of an inhibited caspase-3 pathway on apoptosis in convex and concave sites VSMCs of ascending aortic tissue in vitro. Specimens from the convex and concave sites of ascending aortic aneurysm were collected from nine patients with BAV (mean age 58.7+/-14.8). Cultured VSMCs were characterized morphologically and immunohistochemically. Apoptosis activity was measured in VSMCs using Annexin V-APC with propidium iodide nuclear staining in flow cytometry. To investigate apoptotic modulation, caspase-3 was inhibited by N-acetyl-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO). Apoptosis was initiated by calcium chloride. Inhibition of caspase-3 with Ac-DEVD-CHO protected VSMCs against calcium chloride apoptosis significantly more in the concave site than in the convex site (25.8+/-9.8 versus 38.5+/-8.0% apoptotic cells, p=0.01). Morphological scanning using light microscopy revealed typical VSMCs. We provide evidence that VSMCs show a different behavior with respect to apoptosis in the concave versus the convex sites in BAV ascending aortic aneurysm. Inhibition of caspase-3 resulted in a significantly increased protection of VSMCs against apoptosis in the concave site compared with the convex site in ascending aortic aneurysm in BAV. These findings may have some implications on understanding aneurysmal formation and its potential modulation.

In vitro cultivation and immunogenicity of human cardiac valve endothelium.

Abstract Endothelial cells were derived from aortic and mitral valves (n = 17) by collagenase digestion and subsequently cultivated in RPMI medium supplemented with 20% fetal calf serum. The cells were stained in an alkaline phosphatase‐anti‐alkaline phosphatase stain for the expression of MHC Class I and Class II antigens, ICAM‐1, ELAM‐1, F VIII, and H/Y. The endothelium showed a strong expression of Class I, H/Y, and ICAM‐1 molecules, and weak expression of MHC Class II molecules. In contrast to vascular endothelium that is known to express F VIII constitutively, cardiac valve endothelium was found to be negative. F VIII and ELAM‐1 were only expressed after stimulation with recombinant interferon‐gamma. To analyze the immunogenicity of valve endothelium, cells were used as stimulator cells in a mixed cell culture reaction using lymphocytes as responder cells. Endothelial cells had a 2 to 3 times higher stimulatory effect than peripheral blood lymphocytes. These data allow speculation on whether the observed degeneration of homografts can be reduced if HLA matching is performed prior to valve implantation.

Pathway Analysis of Differentially Expressed Genes in Patients with Acute Aortic Dissection

Background Acute aortic dissection (AAD) is a life-threatening condition with high mortality and a relatively unclarified pathophysiological mechanism. Although differentially expressed genes in AAD have been recognized, interactions between these genes remain poorly defined. This study was conducted to gain a better understanding of the molecular mechanisms underlying AAD and to support the future development of a clinical test for monitoring patients at high risk. Materials and Methods Aortic tissue was collected from 19 patients with AAD (mean age 61.7 ± 13.1 years), and from eight other patients (mean age 32.9 ± 12.2 years) who carried the mutated gene for Marfan syndrome (MS). Six patients (mean age 56.7 ± 12.3 years) served as the control group. The PIQOR™ Immunology microarray with 1076 probes in quadruplicates was utilized; the differentially expressed genes were analysed in a MedScan search using PathwayAssist software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and protein analysis were performed. Results Interactions of MS fibrillin-1 (FBN1) in the MedScan pathway analysis showed four genes, fibulin-1 (FBLN1), fibulin-2 (FBLN2), decorin (DCN) and microfibrillar associated protein 5 (MFAP5), which were differentially expressed in all tissue from AAD. The validation of these genes by qRT-PCR revealed a minimum of three-fold downregulation of FBLN1 (0.5 ± 0.4 vs. 6.1 ± 2.3 fold, p = 0.003) and of DCN (2.5 ± 1.0 vs. 8.5 ± 4.7 fold, p = 0.04) in AAD compared to MS and control samples. Conclusions Downregulation of fibrillin-1 (FBN1) may weaken extracellular components in the aorta and/or interfer with the transmission of cellular signals and eventually cause AAD. Additional research on these four identified genes can be a starting point to develop a diagnostic tool.

Elevation of Matrix Metalloproteinases in Different Areas of Ascending Aortic Aneurysms in Patients with Bicuspid and Tricuspid Aortic Valves

Our aim is to investigate the elevation of matrix proteins in tissues obtained from distal, above the sinotubular junction (proximal), concave, and convex sites of aneurysms in the ascending aorta using a simultaneous multiplex protein detection system. Tissues were collected from 41 patients with ascending aortic aneurysms. A total of 31 patients had a bicuspid aortic valve (BAV), whereas 10 had a tricuspid aortic valve (TAV). Concave and convex aortic site samples were collected from all patients, whereas proximal and distal convexity samples were obtained from 19 patients with BAV and 7 patients with TAV. Simultaneous detection of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was performed at each of the four aortic sites. MMP-2 levels were higher in the concave aortic sites than in the convex aortic sites. In contrast, MMP-8 levels were higher in the convex sites than in the concave sites, as were MMP-9 levels. In both BAV and TAV patients, TIMP-3 levels were higher in the concave sites than in the convex sites. However, TIMP-2 and TIMP-4 levels were significantly elevated in the sinotubular proximal aorta of BAV patients. Simultaneous detection of MMPs and TIMPs revealed different levels at different aortic sites in the same patient.