Doreen Richardt

Anatomic and procedural predictors of paravalvular aortic regurgitation after implantation of the Medtronic CoreValve bioprosthesis.

OBJECTIVES The purpose of this study was to determine the predictors of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI). BACKGROUND TAVI has been associated with a high rate of paravalvular regurgitation, usually mild. Nevertheless, moderate to severe regurgitations still occur and may have negative clinical consequences. METHODS Fifty patients with severe aortic stenosis were recruited and underwent successful TAVI with the Medtronic CoreValve bioprosthesis through the transfemoral route. The end point of this study is the early occurrence of significant AR, defined as the occurrence of grade II or more AR by post-procedural aortography. RESULTS The study populations mean age was 80.5 ± 7.9 years, with a mean aortic valve area of 0.64 ± 0.17 cm². Post-procedural AR was absent in 3 patients and was grade I in 27 patients, grade II in 13 patients, and grade III in 7 patients. Using univariate analysis, the chance of significant AR increased with increasing angle of left ventricular outflow tract to ascending aorta (∠LVOT-AO) (odds ratio: 1.24, p < 0.001). For the depth of the device in relation to the noncoronary cusp, there was a minimum chance of AR corresponding to depth = 9.5 mm (odds ratio: 1.1, p = 0.01). Using multivariate analysis, we found a greater chance of significant AR with a greater angle (odds ratio: 1.24, p = 0.001), and that the chance of significant AR is a minimum when depth of the device in relation to the noncoronary cusp is ∼10 mm (odds ratio: 1.1, p = 0.024). A predictive model was generated, and if 2 ×∠LVOT-AO + (depth to noncoronary cusp - 10)² ≥ 50, the likelihood of occurrence of significant AR could be predicted with a sensitivity of 85% and a specificity of 87%. CONCLUSIONS The occurrence of significant AR after TAVI can be predicted by anatomic and procedural variables. A model such as that presented can be used to select suitable patients for this procedure and guide operators during implantation of the device.

Organotypic slice culture from human adult ventricular myocardium

AIMS Cardiovascular research requires complex and functionally intact experimental models. Due to major differences in the cellular and subcellular composition of the myocardium between species, the use of human heart tissue is highly desirable. To enhance the experimental use of the human myocardium, we established methods for the preparation of vital tissue slices from the adult ventricular myocardium as well as conditions for their long-term preservation in organotypic culture. METHODS AND RESULTS Human ventricular heart samples were derived from surgical specimens excised during a therapeutic Morrow myectomy and cut into 300 μm thick slices. Slices were either characterized in acute experiments or cultured at a liquid-air interface. Viability and functionality were proven by viability staining, enzyme activity tests, intracellular potential recordings, and force measurements. Precision-cut slices showed high viability throughout 28 days in culture and displayed typical cardiomyocyte action potential characteristics, which enabled pharmacological safety testing on the rapid component of the delayed rectifier potassium current (I(Kr)) and ATP-dependent potassium channels throughout the whole culture period. Constant expression of major ion channels was confirmed by quantitative PCR. Acute slices developed excitation-dependent contractions with a clear preload dependency and a β-adrenergic response. Contractility and myosin light chain expression decreased during the first days in culture but reached a steady state with reactivity upon β-adrenergic stimulation being preserved. CONCLUSION Organotypic heart slices represent a multicellular model of the human myocardium and a novel platform for studies ranging from the investigation of molecular interactions to tissue engineering.

Long-Term Results of 203 Young and Middle-Aged Patients With More Than 10 Years of Follow-Up After the Original Subcoronary Ross Operation

BACKGROUND The choice of prosthesis for aortic valve replacement in young and middle-aged patients remains challenging owing to the accelerated degeneration of bioprostheses in these age groups and the risks of thromboembolism and bleeding with mechanical valves. Theoretically, the living pulmonary autograft (Ross operation) would be advantageous. Long-term results of the various Ross techniques are needed for defining the value of this surgical concept. METHODS Of a total of 576 subcoronary Ross patients operated on between June 1994 and June 2011, we report on 203 consecutive subcoronary patients (mean age, 47.2±13.6 years, 155 male, 2,491 patient-years) with a follow-up of at least 10 years (mean, 12.3±2.9 years). RESULTS Early and late mortality were 0.98% (n=2) and 11.4% (n=23). Valve-related mortality was 2.5% (n=5). Survival did not differ from that of the general German population. Freedom from autograft or allograft reoperation was 92.2% at 10 years and 87.1% at 15 years. Five major bleeding (0.20%/patient-year) and 11 thromboembolic events (0.44%/patient-year) occurred in 5 and 10 patients, respectively. Neither a systematic increase in aortic regurgitation nor an increase in root dimensions with time could be observed. In the vast majority of patients, valvular hemodynamics at latest echocardiographic follow-up were excellent. CONCLUSIONS Long-term results of the original subcoronary Ross operation reveal normal survival, excellent hemodynamics, low risk of thromboembolism or bleeding, and small risk for reoperation. These results favor the pulmonary autograft concept in young and middle-aged patients in experienced centers and may serve to better define its role in surgical treatment of aortic valve disease in these patients.

Toward individualized management of the ascending aorta in bicuspid aortic valve surgery: The role of valve phenotype in 1362 patients

OBJECTIVE Decision making regarding the management of the ascending aorta (AA) in patients with a bicuspid aortic valve (BAV) undergoing valve surgery has hardly been individualized and remains controversial. We analyzed our individualized, multifactorial approach, focusing on the BAV phenotype. METHODS In 1362 patients (1044 men) undergoing aortic valve surgery, the BAV phenotypes were intraoperatively classified and retrospectively analyzed. The mean follow-up was 5.4±3.6 years (range, 0-14; 7334 patient-years), and the data were 96.5% complete. The individualized AA management decision process mainly included the AA diameter, age, body surface area, macroscopic AA configuration, and the perceived tissue strength of the aortic wall resulting in 3 AA treatment groups: no intervention, aortoplasty (AoP), and AA replacement (AAR). RESULTS In 906 patients (66.5%), no intervention was performed and 172 (12.6%) and 284 (20.9%) underwent AoP and AAR, respectively. The hospital mortality was 1.1% for no intervention, 0.6% for AoP, and 0.4% for AAR (P=.4). The 10-year survival was similar for all 3 groups and comparable to that of the general population. Five reoperations on the AA occurred, 4 in the no intervention and 1 in the AoP group. BAV type 2/unicuspid patients were younger and more had undergone AAR in absolute numbers and after allowing for the AA diameter. Also, in patients with BAV type 1 LR and regurgitation, AAR was performed more often. CONCLUSIONS The individualized, multifactorial management of AA in patients with BAV during aortic valve surgery leads to excellent results. The threshold AA diameter for intervention (AoP or AAR) varied from 34 to 51 mm (mean, 43.9). BAV type 2/unicuspid and BAV type 1 LR with regurgitation emerged as determinants for more liberal AAR in our practice. Longer term follow-up is necessary to confirm our conclusions.

Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning

OBJECTIVE Numerous studies support the concept of impaired postischemic sympathetic neurotransmission in the heart. We hypothesized that postischemic neuronal dysfunction (neuronal stunning) is caused by a transient suppression of exocytotic norepinephrine (NE) release from sympathetic nerve terminals. Furthermore, we assessed the role of presynaptic adenosine-receptors and alpha2-adrenoceptors in neuronal stunning. METHODS AND RESULTS Exocytotic NE release was induced by two electrical field stimulations (S(1) and S(2)) in isolated perfused rat hearts. S(1) was performed under baseline conditions and S(2) either during or following intervention. Results are expressed as mean S(2)/S(1) ratios+/-S.E.M. Stepwise increase of global ischemic periods (10, 20, and 30 min) induced a progressive suppression of NE release in the postischemic hearts, which was reversible during reperfusion. Both the degree and duration of NE suppression was dependent on the extent of the preceding ischemic period. Following 10-min ischemia complete recovery of NE release was achieved after 5-min reperfusion (1.07+/-0.12), whereas 5-min reperfusion did not restore NE release after 30 min (0.36+/-0.07) of ischemia. The adenosine-receptor antagonists 8-phenyltheophylline (8-PT; non-selective) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; adenosine A1-receptor subtype selective) significantly increased NE release after 30-min ischemia and 5-min reperfusion (0.78+/-0.06 and 0.64+/-0.07), while in the same experimental protocol blockade of alpha2-adrenoceptors by yohimbine failed to restore the postischemic release (0.24+/-0.06). In non-ischemic hearts the adenosine analogue R(-)N(6)-(2-phenylisopropyl)adenosine (R-PIA) resulted in a marked suppression of NE release (0.61+/-0.07). The inhibitory effect of R-PIA and 2-chloro-N(6)-cyclopentyladenosine (CCPA; adenosine A1-receptor subtype selective agonist) persisted 5 min after cessation of R-PIA (0.62+/-0.05) and CCPA (0.58+/-0.04). Activation of alpha2-adrenoceptors by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) also caused a reduction of NE release (0.50+/-0.02), but the release increased to control levels 5 min after cessation of UK 14,304 (0.90+/-0.06). CONCLUSIONS The results establish the phenomenon of neuronal stunning in terms of a postischemic suppression of exocytotic NE release and provide evidence that neuronal stunning is mediated by endogenous adenosine through activation of presynaptic adenosine A1-receptors.

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.

A new sinus prosthesis for aortic valve-sparing surgery maintaining the shape of the root at systemic pressure.

PURPOSE We describe a new prosthetic graft aiming to restore normal valve configuration in systemic circulation. In vitro evaluation data and first clinical results are presented. DESCRIPTION The aortic valve consists of three separate leaflets and sinuses of Valsalva interconnected through three straight interleaflet triangles. This shape has important implications on valve function. EVALUATION In vitro tests showed nearly normal hemodynamics, although root distensibility was decreased and bending deformation of the leaflets was increased due to the nonflexibility of the graft material. However, the anatomical shape of the aortic root was well preserved in vitro and also in vivo without contact of leaflets to the prosthesis wall. CONCLUSIONS This new sinus prosthesis maintains normal configuration of the aortic root with three distinct sinuses of Valsalva and straight commissural pillars in systemic circulation. The noncompliant material induces abnormal leaflet bending during systole, but leaflets do not collide with the wall of prosthesis.

Residual and Progressive Aortic Regurgitation After Valve-Sparing Root Replacement: A Propensity-Matched Multi-Institutional Analysis in 764 Patients

BACKGROUND Residual/progressive aortic regurgitation (rAR, pAR) after valve-sparing aortic root replacement (V-SARR) can lead to reoperations. We sought to characterize risk factors of mild rAR and pAR after V-SARR in a multicenter cohort. The effect of additional cusp repair on valve function was analyzed using propensity matching. METHODS A total of 1,015 patients after V-SARR were identified with (n = 288, 28%) or without additional cusp/commissure repair (n = 727, 72%) at four cardiac units in Germany. A total of 764 patients fulfilling transthoracic echocardiography follow-up-criteria comprised the study cohort. Logistic regression was used for risk factor analysis with endpoints rAR, new onset AR, and pAR. t tests and analyses of variance were used for between-group differences. The effects of additional cusp repair on valve function were studied comparing propensity-matched quintiles. RESULTS The incidence of rAR was 29%, with influencing factors aneurysm size (p = 0.07) and preoperative aortic valve function (p = 0.08). It was found more often among nonsyndromic patients (34% vs. 14%; OR, 0.4; p < 0.001). Progression of rAR was detectable in 30% after a mean of 4.3 years. The progression rate of rAR ∼ 0.3 grades per patient-year within the first 5 years. When quintiles identified by propensity score were compared, additional cusp repair was linked to new onset AR (p = 0.016) while it was not linked to rAR (p = 0.14) or pAR (p = 0.5). CONCLUSIONS The incidences of rAR and pAR are considerable after V-SARR. Patients should be operated on before large aneurysms are present. New onset AR after an initially good functional result is more likely after an additional cusp repair, while rAR and pAR are not influenced by cusp repair.

First clinical results with the new sinus prosthesis used for valve-sparing aortic root replacement.

OBJECTIVES Sinuses of Valsalva are important in assuring the physiological function of the aortic valve. This study evaluates short-term clinical results of the reimplantation technique for aortic valve-sparing root replacement using a new prosthesis with three separate sinuses of Valsalva (sinus prosthesis). METHODS Between February 2009 and February 2011, a total of 23 patients (20 m/3 f; mean age 52 ± 14.8 years; range 24-70 years) with aortic root aneurysm underwent aortic valve-sparing procedures according to the David reimplantation technique using the new sinus prosthesis. Eighteen patients had tricuspid and five patients bicuspid aortic valves. All patients received clinical as well as echocardiographic examinations postoperatively (mean 13 ± 9.3 months; 0.3-28 months). RESULTS There was no death and no reoperation of the aortic valve. At latest follow-up, most patients were in New York Heart Association class I (n = 22; 95.7%). In 95.7% aortic valve regurgitation (AR) was 0 or 1+; one patient had AR 2+. Pressure gradients were between the normal range (mean pressure gradient 4.7 ± 1.9 mmHg). Echocardiographic images demonstrate physiological aortic root dimensions and configuration with three separate sinuses of Valsalva without systolic contact of leaflets to the wall. CONCLUSIONS The new sinus prosthesis provides near normal root geometry and hemodynamics in valve-sparing aortic root replacement using the reimplantation technique, applicable for tricuspid and also bicuspid aortic valves.

Acute kidney injury after transcatheter aortic valve implantation: Impact of contrast agents, predictive factors, and prognostic importance in 203 patients with long-term follow-up

BACKGROUND Acute kidney injury (AKI) frequently occurs following transcatheter aortic valve implantation (TAVI) and has been related to a worse outcome. We investigated the importance of contrast medium composition, either iso-osmolar (IOCM) or low-osmolar (LOCM) and assessed predictors for AKI after TAVI. METHODS AND RESULTS We assessed AKI in 203 TAVI patients treated mainly with trans-femoral implantation and analgosedation. A total of 100 patients received IOCM and 103 LOCM. AKI was defined according to the Valve Academic Research Consortium. Following TAVI, 39 patients (19.2%) developed AKI; 17.0% of the IOCM and 21.4% of the LOCM group (p=0.43). The only independent predictor for AKI was baseline serum creatinine [odds ratio (OR) 0.26, 95% confidence interval (CI) 0.01-0.64, p=0.002]. Patients with advanced AKI (stages 2 and 3) post-TAVI had significantly higher mortality at 2 years (log rank p<0.001), whereas patients with AKI stage 1 had a similar long-term outcome to non-AKI patients. CONCLUSIONS Following TAVI, we observed no difference in the occurrence of AKI between IOCM and LOCM. Baseline creatinine was the only independent predictor of AKI, and patients who developed advanced AKI had significantly higher mortality at 2 years.