Dysregulation of Endothelial Nitric Oxide Synthase Does Not Depend on Hemodynamic Alterations in Bicuspid Aortic Valve Aortopathy.

Background Bicuspid aortic valves (BAVs) predispose to ascending aortic aneurysm. Turbulent blood flow and genetic factors have been proposed as underlying mechanisms. Endothelial nitric oxide synthase (eNOS) has been implicated in BAV aortopathy, and its expression is regulated by wall shear stress. We hypothesized that if turbulent flow induces aneurysm formation in patients with a BAV, regional differences in eNOS expression would be observed in BAVs. Methods and Results Ascending aortic specimens were harvested intraoperatively from 48 patients with tricuspid aortic valve (19 dilated, 29 nondilated) and 38 with BAV (28 dilated, 10 nondilated) undergoing cardiac surgery. eNOS mRNA and protein concentration were analyzed at the convex and concave aortic wall. In nondilated aortas, eNOS mRNA and protein concentration were decreased in BAV compared with tricuspid aortic valve (all P<0.05). eNOS expression was increased in association with dilation in BAV aortas (P=0.03), but not in tricuspid aortic valve aortas (P=0.63). There were no regional differences in eNOS mRNA or protein concentration in BAV aortas (all P>0.05). However, eNOS expression was increased at the concave wall (versus convexity) in tricuspid aortic valve dilated aortas (all P<0.05). Conclusions Dysregulated eNOS occurs independent of dilation in BAV aortas, suggesting a potential role for aberrantly regulated eNOS expression in the development of BAV-associated aneurysms. The absence of regional variations of eNOS expression suggests that eNOS dysregulation in BAV aortas is the result of underlying genetic factors associated with BAV disease, rather than changes stimulated by hemodynamic alterations. These findings provide insight into the underlying mechanisms of aortic dilation in patients with a BAV.

Sinus Plication to Improve Valve Configuration in Bicuspid Aortic Valve Repair-Early Results.

BACKGROUND: Previous experience with repair of the regurgitant bicuspid aortic valve (BAV) has shown a strong influence of commissural orientation on repair durability. We have modified commissural orientation by asymmetric plication of the fused sinuses. We analyzed the results of the modified technique. METHODS: Between 2009 and 2014, 35 patients with BAV and commissural orientation of no more than 160° underwent aortic valve repair, including plication of the fused sinuses and circular annuloplasty. The control group consisted of 21 historic controls undergoing operations between 2000 and 2008 but without sinus plication; subcommissural plication was used as annuloplasty. The groups were similar in most respects; differences existed in preoperative annular diameter, prevalence of complete fusion, use of a pericardial patch, and plication of the fused cusp. RESULTS: At discharge the degree of aortic regurgitation (AR) was significantly lower in the study group (p = 0.004). Survival after 5 years was 100% in the study group and 95.2% in the control group after 5 and 10 years. Five-year freedom from reoperation in the study group was 93.0% and 57.1% in the control group (p = 0.0013); freedom from valve replacement was 95.8% and 79.3% (p = 0.036). Freedom from recurrent AR grade II or higher was 67.1% in the study group and 33.3% in the control group (p = 0.0024). Mean postoperative peak gradient was significantly lower in the study group (14.3 ± 6.5 mm Hg versus 28.9 ± 18.5 mm Hg, p = 0.003). CONCLUSIONS: Plicating the fused sinuses and thus reducing root circumference in the fused part changes commissural orientation of the BAV which leads to better short- and midterm stability in BAV repair.

Physical and mental recovery after conventional aortic valve surgery.

OBJECTIVE: Physical and mental recovery are important factors to consider in the treatment of aortic valve disease, and the process of recovery is not well known. We investigated the course of physical and mental recovery directly after conventional aortic valve surgery. METHODS: In a longitudinal study, 60 patients undergoing elective aortic valve surgery were studied preoperatively and at intervals of 4 weeks after aortic valve surgery. The last measurement was taken 6 months postoperatively. Measurements included the 6-minute walk test and N-terminal pro-B-type natriuretic peptide. Mental recovery was assessed by the Short Form Health Survey and the Hospital Anxiety and Depression Scale. All parameters were compared with published healthy norms. RESULTS: All parameters except for the anxiety score showed a significant decline after the first postoperative measurement at 1 week after aortic valve surgery. The baseline level was restored at 1 to 3 weeks (anxiety, depression, mental quality of life, Borg scale), 4 to 6 weeks (6-minute walk test, physical quality of life), and 9 weeks (N-terminal pro-B-type natriuretic peptide) after the first postoperative week. Significantly better values than preoperatively for the first time were reached at 2 to 3 weeks (anxiety, depression, mental quality of life), 5 weeks (6-minute walk test), 8 weeks (physical quality of life), and 12 weeks (N-terminal pro-B-type natriuretic peptide) after the first postoperative week. At 3 months postoperatively, significant improvements (P < .001) were seen in walk distance (+212 m), dyspnea (-1.11), physical (+12.38) and mental quality of life (+7.71), anxiety (-3.74), and depression (-3.62) compared with the first week postoperatively. At 6 months postoperatively, all parameters were significantly improved compared with preoperative data and, except for the N-terminal pro-B-type natriuretic peptide value, significantly better or equal compared with published healthy norms. CONCLUSIONS: After conventional aortic valve surgery, the most pronounced recovery was seen in the first 6 weeks postoperatively. Physical quality of life and N-terminal pro-B-type natriuretic peptide required a prolonged time for a complete recovery.

Vasopressin as Therapy During Nonocclusive Mesenteric Ischemia.

BACKGROUND: Vasopressin is used as an adjunct to norepinephrine to support blood pressure in vasodilatory shock after cardiopulmonary bypass (CPB). In this study, we report our observation of vasopressin treatment in 11 patients with nonocclusive mesenteric ischemia (NOMI). METHODS: In an observational cohort study, 78 patients were studied after having been treated for NOMI with intraarterial iloprost infusion after elective cardiac operation. All patients received norepinephrine as vasopressor for marked vasodilation. In 11 patients mean arterial pressure could not be maintained with norepinephrine alone (≤0.4 µg · kg(-1) · min(-1)), and vasopressin was given in addition to norepinephrine as a rescue therapy. The 11 patients (Vaso) and the remaining 67 patients (Nor) were analyzed for clinical improvement after initiation of NOMI treatment, on the following days 1 and 2, and for hospital survival. Intestinal perfusion was controlled by mesenteric angiography. RESULTS: Before initiation of NOMI treatment Vaso patients had significantly higher doses of norepinephrine than the Nor patients (Vaso, 0.65 ± 0.20 µg · kg(-1) · min(-1); Nor, 0.20 ± 0.13 µg · kg(-1) · min(-1); p < 0.001), and their diagnostic score of the angiography was higher (Vaso, 5.4 ± 1.1 points; Nor, 3.5 ± 2.1 points; p = 0.004). After 2 days of NOMI treatment, Vaso patients had improved intestinal perfusion in the control angiography (Vaso, 3.8 ± 1.5 points) and significantly lower doses of norepinephrine than the Nor patients (Vaso, 0.28 ± 0.12 µg · kg(-1) · min(-1); Nor, 0.53 ± 0.34 µg · kg(-1) · min(-1); p = 0.002). All patients survived in the Vaso group; in the Nor group, 17 of 67 patients died in the hospital. CONCLUSIONS: Vasopressin administration during NOMI treatment after CPB seems to improve small intestine perfusion and appears be to associated with improved hospital survival.

[Quality of life or life expectancy? Criteria and sources of information in the decision-making of patients undergoing aortic valve surgery]. / Lebensqualität oder Lebenserwartung? Kriterien und Informationsquellen für die Entscheidungsfindung bei Patienten im Vorfeld von Aortenklappenoperationen.

OBJECTIVES: Physicians are expected to involve patients adequately in the decision-making process prior to surgery. To this end, it is essential to have knowledge about the potential reasons for such a decision. In this study we investigated which information sources and decision criteria are important to patients prior to aortic valve surgery. METHODS: A consecutive sample of 468 patients (70.1%m, aged 66.9±14.2 years) was examined 2 years after aortic valve replacement or reconstruction with a self-developed questionnaire. RESULTS: Preoperative discussion with a cardiologist or a cardiac surgeon was the information source patients used most frequently and felt to be the most helpful. The most important decision criterion was quality of life, followed by life expectancy and likelihood of reoperation. Two years postoperatively, 97.3% of the patients were satisfied with their decision. CONCLUSIONS: Preoperative counseling by a physician plays an essential role in the decision-making process prior to cardiac surgery. Patients want to be involved in decision-making, though they do not want to bear the full responsibility.

Elevated endothelin-1 level is a risk factor for nonocclusive mesenteric ischemia.

OBJECTIVE: Nonocclusive mesenteric ischemia may occur after cardiac surgery, commonly in conjunction with the use of cardiopulmonary bypass. Some evidence suggests that endothelin-1 serum levels are increased in patients with mesenteric ischemia, but the association of endothelin-1 and nonocclusive mesenteric ischemia has not been studied. The objective was to investigate whether elevated levels of endothelin-1 could be found in patients exhibiting nonocclusive mesenteric ischemia. METHODS: In an observational cohort study, nonocclusive mesenteric ischemia developed in 78 of 865 patients undergoing elective cardiac surgery. Control patients were identified from the cohort through 1:1 propensity score matching. Preoperative and postoperative endothelin-1 serum levels were determined by means of enzyme-linked immunosorbent assay. Odds ratios (with 95% confidence interval) were calculated by logistic regression analyses to determine the risk of endothelin-1 for the development of nonocclusive mesenteric ischemia. RESULTS: Patients with nonocclusive mesenteric ischemia had higher preoperative (11.3 vs 9.3 pg/mL; P = .001) and postoperative (15.7 vs 11.1 pg/mL, P < .001) levels of endothelin-1 than the controls. The probability of developing nonocclusive mesenteric ischemia increased with each picogram/milliliter endothelin-1 level preoperatively (odds ratio, 1.29; 95% confidence interval, 1.12-1.49) and each picogram/milliliter postoperatively (odds ratio, 2.04; 95% confidence interval, 1.54-2.72). Receiver operating characteristic analyses showed that elevated endothelin-1 serum levels had a high accuracy to predict nonocclusive mesenteric ischemia (optimal cutoff value of 14.5 pg/mL, area under the curve of 0.77, sensitivity 51%, and specificity 94%). CONCLUSIONS: Endothelin-1 seems to predispose patients undergoing cardiac surgery to develop nonocclusive mesenteric ischemia. In addition, it may be a useful marker to identify patients at risk for nonocclusive mesenteric ischemia after cardiac surgery.

GATA5 and endothelial nitric oxide synthase expression in the ascending aorta is related to aortic size and valve morphology.

BACKGROUND: The pathogenesis of aortic dilatation in patients with congenital aortic valve anomalies is poorly understood. Recent studies suggest that alterations of gene expression may be related to ascending aortic aneurysm formation in these patients. Knockout of endothelial nitric oxide synthase (eNOS) and GATA5 is associated with bicuspid aortic valves in mice. To study the role of eNOS and GATA5 in human congenital aortic valve disease and aortic dilatation, we investigated their gene expression in aortic tissue from patients with unicuspid, bicuspid, and tricuspid aortic valves. METHODS: Samples from 84 patients (33 tricuspid, 32 bicuspid, and 19 unicuspid) were harvested intraoperatively from the ascending aorta. GATA5 and eNOS expression was determined by real-time polymerase chain reaction. RESULTS: GATA5 and eNOS expression in the aortic wall from patients with unicuspid aortic valves (GATA5: mean [M], 2.14; standard deviation [SD], 1.72; eNOS: M, 3.40; SD, 3.83) was significantly higher than in tricuspid aortic valves (GATA5: M, 1.12; SD, 0.80; eNOS: M, 1.00; SD, 0.74; each p < 0.05). Patients with bicuspid aortic valves (GATA5: M, 1.29, SD, 1.33; eNOS: M, 1.66; SD, 1.31) had a significantly higher eNOS expression than patients with tricuspid aortic valves (p < 0.05). The expression levels of eNOS and GATA5 correlated positively with each other and negatively with the ascending aortic diameter. CONCLUSIONS: Our data suggest that GATA5, possibly through upregulation of eNOS, plays a role in the development of aortic dilatation in patients with unicuspid and bicuspid aortic valves. The differential gene expression in patients with unicuspid compared with bicuspid aortic valves suggests that the pathogenesis of both aortic valve anomalies may be different.

Identification of reference genes for quantitative RT-PCR in ascending aortic aneurysms.

Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue.

Early results with annular support in reconstruction of the bicuspid aortic valve.

OBJECTIVE: Repair of the bicuspid aortic valve may be performed in aortic regurgitation and aneurysm. Dilatation of the atrioventricular junction has been identified as a risk factor for repair failure, and we have used suture annuloplasty to correct atrioventricular junction enlargement. The objective was to compare the early results of aortic repair with and without annuloplasty. METHODS: Between November 1995 and January 12, a total of 559 patients were treated with bicuspid aortic valve repair for predominant regurgitation (n = 389), aortic aneurysm (n = 158), or acute dissection (n = 12). Isolated valve repair (aortic valve repair) was performed for aortic valve regurgitation with preserved aortic dimensions (n = 208) and sinotubular junction remodeling plus valve repair for aortic aneurysm and preserved root size (n = 116). Root remodeling was used for dilatation involving the root (n = 235). In 193 patients, dilatation of the atrioventricular junction (>27 mm) was corrected with suture annuloplasty. RESULTS: Hospital mortality was 0.5% (n = 3); 2 patients required pacemaker implantation. Reoperation was necessary for recurrent regurgitation (n = 54) or stenosis (n = 2); 10-year freedom from reoperation was 82% but was inferior after isolated valve repair (70%, P = .007) compared with the 2 other techniques. Application of suture annuloplasty improved 3-year freedom from reoperation after isolated repair (84%) to 92% (P = .07). In all groups, the proportion of patients with no or trivial regurgitation was significantly higher with annuloplasty. CONCLUSIONS: Preservation of the bicuspid aortic valve is feasible in many patients. Long-term stability of the repaired valves is good; the negative impact of a dilated atrioventricular junction can be reduced by suture annuloplasty.

Causes and management of aortic valve regurgitation after aortic valve reimplantation.

OBJECTIVE: Recurrent aortic regurgitation can occur after valve-preserving aortic replacement. Little is known about the exact mechanisms of valve failure and the best reoperative strategies. We analyzed our experience with reoperation after aortic valve reimplantation. METHODS: From November 1995 to August 2011, 13 patients (10 men; age, 18-58 years) underwent reoperation for valve failure after aortic valve reimplantation. The reason for reoperation was aortic regurgitation in 11 and endocarditis in 2 after 6 weeks to 13 years. The morphologic causes of regurgitation were cusp prolapse in 6, cusp retraction in 4, cusp perforation in 6, inadequate commissural height in 5, commissural dehiscence in 2, and inadequate valve configuration in 1, alone or combined. The patients were treated by valve replacement (n = 4) or cusp repair (n = 2). In 3 patients, composite replacement of the valve and root was necessary, in 1 with a pulmonary autograft. In 4 patients the aortic valve was spared. All patients were followed up regularly. RESULTS: No patient died early; 1 patient died 4 years after reoperation. One patient required reoperation 2 years after the cusp repair procedure. All patients with repeat valve-preserving root replacement had stable valve function postoperatively. The 5-year survival rate after reoperation was 86% ± 13%. The 5-year rate of freedom from valve-related complications was 78% ± 14%. CONCLUSIONS: Recurrent aortic regurgitation early after aortic valve reimplantation frequently involves cusp prolapse and a low commissural height; later, cusp retraction becomes more important. Reoperation within the first 6 postoperative months allows for preservation of the native aortic valve; however, beyond this period, valve replacement within the graft will mostly be required.

Cusp height in aortic valves.

OBJECTIVES: Successful aortic valve repair must normalize cusp and root dimensions. Limited information is available on the normal dimensions of human cusps, in particular the cusp height. METHODS: The cusp height was measured intraoperatively in 621 patients during aortic valve repair procedures. A tricuspid anatomy was present in 329 patients and bicuspid in 286 patients. In addition, patient age, gender, height, weight, preoperative degree of aortic regurgitation, and aortic dimensions were recorded. The data were analyzed for possible interrelation between the cusp height and clinical variables. RESULTS: In the bicuspid valves, the geometric height of the nonfused cusp ranged from 15 to 30 mm (mean, 23.8 ± 2.0). Significant correlations were found between the cusp height and all clinical variables. In the tricuspid valves, the height of the noncoronary cusp ranged from 14 to 28 mm (mean, 20.7 ± 2.2). The height of the left coronary cusp varied from 12 to 25 mm (mean, 20.0 ± 2.1) and that of the right coronary cusp from 12 to 25 mm (mean, 20.0 ± 2.1). The noncoronary cusp was significantly greater than the left and the right coronary cusp (P = .000). No difference was found between the left and right cusps (P = .513). Significant correlations between the geometric height and clinical parameters were found for most clinical variables, excluding the degree of aortic regurgitation. CONCLUSIONS: We found the cusp height was larger than previously published. It shows marked variability and correlates with the clinical variables. These data might serve as the basis for decision making in aortic valve repair.

Risk factors for nonocclusive mesenteric ischemia after elective cardiac surgery.

OBJECTIVE: Nonocclusive mesenteric ischemia (NOMI) may occur after cardiopulmonary bypass. It is crucial to early identify patients who are at risk of developing this complication. The aim of this prospective study was to evaluate perioperative risk factors in a large cohort of patients undergoing elective cardiac surgery. METHODS: From January 1, 2010, to March 31, 2011, all patients scheduled for elective cardiac surgery were screened for participation in this trial. If NOMI was suspected, arterial angiography was performed. NOMI and non-NOMI patients were compared with respect to all variables assessed in this study. Additionally, odds ratios were calculated. Linear discriminant analyses as well as logistic regression analyses were performed to develop a model that identifies patients at risk for developing NOMI. RESULTS: Eight hundred sixty-five patients were included in the study, of whom 78 developed NOMI. Among preoperative parameters, renal insufficiency, diuretic therapy, and age >70 years showed the highest odds ratios for postoperative NOMI. The highest odds ratios for development of NOMI were observed with postoperative variables. In particular, the need for intra-aortic balloon pump support and serum lactate concentrations >5 mmol/L proved to be serious risk factors. Using a linear discriminant analysis with 7 variables, 92.3% of patients were correctly classified (sensitivity 76.9%, specificity 93.8%). CONCLUSIONS: A high index of suspicion for NOMI in patients with the above-mentioned risk factors may decrease the diagnostic and therapeutic delay. To identify at-risk patients the developed risk equation is a useful tool with a high specificity.