Peter Matt

Circulating Transforming Growth Factor-β in Marfan Syndrome

Background— Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-&bgr; (TGF-&bgr;). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-&bgr; activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-&bgr; might be mirrored in circulating TGF-&bgr; concentrations. Methods and Results— Serum obtained from MFS mutant mice (Fbn1C1039G/+) treated with losartan was analyzed for circulating TGF-&bgr;1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-&bgr;1 concentrations increased with age and were elevated in older untreated Fbn1C1039G/+ mice compared with wild-type mice (P=0.01; n=16; mean±SEM, 115±8 ng/mL versus n=17; mean±SEM, 92±4 ng/mL). Losartan-treated Fbn1C1039G/+ mice had lower total TGF-&bgr;1 concentrations compared with age-matched Fbn1C1039G/+ mice treated with placebo (P=0.01; n=18; 90±5 ng/mL), and circulating total TGF-&bgr;1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-&bgr;1 levels and aortic root diameters in Fbn1C1039G/+ and wild-type mice (P=0.002). In humans, circulating total TGF-&bgr;1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15±1.7 ng/mL versus n=74; 2.5±0.4 ng/mL). MFS patients treated with losartan (n=55) or &bgr;-blocker (n=80) showed significantly lower total TGF-&bgr;1 concentrations compared with untreated MFS patients (P≤0.05). Conclusions— Circulating TGF-&bgr;1 concentrations are elevated in MFS and decrease after administration of losartan, &bgr;-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.

Recent advances in understanding Marfan syndrome: Should we now treat surgical patients with losartan?

OBJECTIVE Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome. METHODS Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression. RESULTS It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome. CONCLUSION There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.

Transfusion of allogeneic blood products in proximal aortic surgery with hypothermic circulatory arrest: effect of thromboelastometry-guided transfusion management.

OBJECTIVES Proximal aortic surgery with hypothermic circulatory arrest (HCA) commonly involves perioperative transfusion of allogeneic blood products, including red blood cells, plasma, and platelets. The authors hypothesized that surgery with HCA could be performed without allogeneic blood products and that a thromboelastometry-guided algorithm would reduce the transfusion of allogeneic blood products. DESIGN A retrospective analysis of prospectively collected data. Patients with and without thromboelastometry guidance were compared by case-control analysis (n = 62 matched patients) and multivariate regression (n = 194 patients). SETTING Single-center university hospital. PARTICIPANTS This study included 194 patients undergoing elective and emergent procedures with HCA involving the proximal aorta. INTERVENTIONS A thromboelastometry-guided treatment algorithm during surgery was used in 153 patients (79%), and conventional coagulation management was used in 41 patients (21%). MEASUREMENTS AND MAIN RESULTS During surgery and the following 24 hours, allogeneic blood products were transfused in 106 patients (55%). Median (interquartile range) number of allogeneic blood products transfused was 1 unit (0-6 units). Case-control analysis showed lower transfusion rates of red blood cells, plasma, and any allogeneic blood product (all p<0.050) in patients with thromboelastometry guidance. In the multivariate analysis, thromboelastometry guidance was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.84; p = 0.025) for the transfusion of any allogeneic blood product. The use of thromboelastometry was not associated with adverse events (odds ratio 0.72; 95% confidence interval, 0.27-1.90; p = 0.507). CONCLUSIONS Allogeneic blood products were avoided in a proportion of patients. The findings further suggest that thromboelastometry-guided coagulation management promoting the use of coagulation factor concentrates decreased the use of allogeneic blood products during complex cardiac surgery.

A new cable-tie-based sternal closure device: infectious considerations

OBJECTIVES To determine the difference in sternal infection and other infectious events between conventional wire and cable-tie-based closure techniques post-sternotomy in a collective of patients after cardiac surgery. METHODS The sternal ZipFix™ (ZF) system consists of a biocompatible poly-ether-ether-ketone (PEEK) cable-tie that surrounds the sternum through the intercostal space and provides a large implant-to-bone contact. Between 1 February 2011 and 31 January 2012, 680 cardiac operations were performed via sternotomy at our institution. After the exclusion of operations for active endocarditis and early mortality within 7 days, 95 patients were exclusively closed with ZF and could be compared with 498 who were closed with conventional wires (CWs) during the same period. A multivariable logistic regression analysis, including body mass index, renal impairment and emergency as suspected confounders and inverse propensity weights was performed on the infection rate. RESULTS Total infection rate was 6.1%, with a total of 36 diagnosed sternal infections (5 in ZF and 31 in CW). Comparing ZF with CW with regard to sternal infection, there is no statistically significant difference related to the device (odds ratio: 0.067, confidence interval: 0.04-9.16, P=0.72). The propensity modelling provided excellent overlap and the mean propensity was almost the same in both groups. Thus, we have observed no difference in receiving either ZF or CW. No sternal instability was observed with the ZF device, unlike 4/31 patients in the CW group. The overall operation time is reduced by 11 min in the ZF group with identical perfusion and clamping times. CONCLUSIONS Our study underlines a neutral effect of the sternal ZipFix™ system in patients regarding sternal infection. Postoperative complications are similar in both sternal closure methods. The cable-tie-based system is fast, easy to use, reliable and safe.

Is close radiographic and clinical control after repair of acute type A aortic dissection really necessary for improved long-term survival?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether radiographic and clinical control after surgery for acute type A aortic dissection (AAD) is needed for improved long-term survival. Altogether, 118 relevant papers were identified using the reported search, of which seven represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that most patients after surgery for AAD remain at risk for dissection-related aortic complications. Late aortic growth is often slow and linear, but the occurrence of major aortic events is unpredictable and can initially present more than a decade postoperatively. Risk factors for rapid late aortic enlargement and reoperations include patent or partially thrombosed false lumen, large aortic size, Marfan syndrome and younger age. Whether performing a more extensive first procedure (e.g. aortic arch replacement±elephant trunk) can be translated into improved outcome and a lower incidence of aorta-related reoperations remains to be elucidated. Aortic reoperation rates range between 10% and >20% within the first 10 years. Optimal systolic blood pressure control (<120 mmHg), including β-blocker therapy, seems to decrease late aortic dilatation and the incidence of aortic reoperations. Close and careful lifelong surveillance of patients after AAD repair including radiographic and clinical controls to evaluate the status of the remaining aorta, and thus to facilitate adaptations of medical therapy and planning of timely reprocedures seems mandatory for improved long-term survival. A suggested timeframe for computed tomographic (CT) imaging after surgery for AAD is before discharge, at six and 12 months postdissection and, if stable, annually thereafter. Patients with large aneurysms (aortic diameter≥50 mm) should be maintained at radiographic intervals of six months or less. If the thoracic aneurysm is moderate in size and remains stable over time, magnetic resonance imaging instead of CT-scanning is reasonable to minimize the patients radiation exposure.

Plicated Patch Repair for Acquired Gerbode Defect Involving the Tricuspid Valve

Gerbodes defect, a left ventricular-to-right atrial communication, with involvement of the tricuspid valve acquired after bacterial endocarditis can be challenging to repair. We report a modified technique for a shunt closure and reconstruction of the tricuspid valve using a plicated bovine pericardial patch. Combining such a repair with a left ventricular patch resulted in a complete defect closure and competent tricuspid valve without regurgitation.

Murine Model of Surgically Induced Acute Aortic Dissection Type A

OBJECTIVES This study aimed at developing a murine model of surgically induced acute aortic dissection type A for investigation of the formation and progression of acute aortic dissection and to test whether this system could be used for biomarker discovery. METHODS Adult fibrillin-1 deficient, Fbn1(C1039G/+) mice and wild-type mice were anesthetized, ventilated, and the ascending aorta exposed via hemisternotomy. We hypothesized that acute aortic dissection could be induced either by injecting autologous blood into the aortic wall or by injury to the wall with aortic clamping. Echocardiography was done preoperatively, and serum samples were collected before and 30 minutes after the operation and analyzed by enzyme-linked immunosorbent assay. RESULTS Echocardiography revealed larger aortic root diameters in Fbn1(C1039G/+) compared with wild-type mice (P = .001). Histologic examination showed that aortic clamp injury but not injection of blood leads to large intimal tears, disruption of aortic wall structures, and localized dissection of the aortic media in Fbn1(C1039G/+) mice. Acute aortic dissection developed in 4 of 5 Fbn1(C1039G/+) mice versus 0 of 5 wild-type mice after aortic clamping (P < .01). Elastin staining showed higher elastic fiber fragmentation and disarray in Fbn1(C1039G/+) compared with wild-type mice. Enzyme-linked immunosorbent assay analysis revealed elevated circulating transforming growth factor beta1 concentrations after induction of acute aortic dissection in Fbn1(C1039G/+) mice (P = .02, 150 +/- 61 ng/mL vs 456 +/- 97 ng/mL), but not in wild-type or sham-operated mice. CONCLUSIONS Aortic clamp injury can induce AAD in Fbn1(C1039G/+), but not in wild-type mice. This murine model of surgically induced acute aortic dissection is highly reproducible and nonlethal in the short term. Using this system, we revealed that circulating transforming growth factor beta1 is a promising biomarker for acute aortic dissection.

Automated fastener versus manually tied knots in minimally invasive mitral valve repair: impact on operation time and short- term results

BackgroundThis study compares the influence of two different annuloplasty attachment suture applications, namely the use of an automated fastener versus manually tied knots using a traditional knot pusher, on total operation time, on cardiopulmonary-bypass time and on cross-clamp time, and on short-term outcome.MethodsSixty patients underwent isolated minimally invasive mitral valve repair in Carpentier Type-II mitral disease with implantation of an annuloplasty ring in combination with correction of the prolapsing leaflet using artificial chords. The first 30 patients after implementation of a novel automated fastener were compared with the last 30 patients corrected with a traditional knot pusher. No significant differences with regard to demographic data (age, gender, NYHA class, ejection fraction, BMI, cardiovascular risk factors) between the two groups were found. All patients received isolated mitral valve repair in the first run. Bretschneider HTK was used for cardioplegic cardiac arrest in all patients.ResultsTransesophageal and transthoracic echocardiography at the end of operation and at discharge revealed no (n = 25), trace (n = 28) or mild (n = 7) residual regurgitation with no evidence of ring dehiscence and without any significant clinical differences between the groups. Cross-clamp, cardiopulmonary-bypass and total- operation time were significantly reduced in the automated fastener group compared to the group using a traditional knot pusher (87.1 ± 17.9 vs. 101.3 ± 17.8; p < 0.01, 138.1 ± 25.6 vs. 152.7 ± 24.9; p < 0.05, and 203.9 ± 31.02 vs. 223.8 ± 29.01; p < 0.01, respectively).ConclusionOur short-term results indicate a safe, reliable and fast application of the novel automated fastener device in combination with significant time savings in cardioplegic arrest and cardiopulmonary bypass.

Proteome analysis in cardiovascular pathophysiology using Dahl rat model.

Dahl salt-sensitive (DS) and salt-resistant (DR) inbred rat strains represent a well established animal model for cardiovascular research. Upon prolonged administration of high-salt-containing diet, DS rats develop systemic hypertension, and as a consequence they develop left ventricular hypertrophy, followed by heart failure. The aim of this work was to explore whether this animal model is suitable to identify biomarkers that characterize defined stages of cardiac pathophysiological conditions. The work had to be performed in two stages: in the first part proteomic differences that are attributable to the two separate rat lines (DS and DR) had to be established, and in the second part the process of development of heart failure due to feeding the rats with high-salt-containing diet has to be monitored. This work describes the results of the first stage, with the outcome of protein expression profiles of left ventricular tissues of DS and DR rats kept under low salt diet. Substantial extent of quantitative and qualitative expression differences between both strains of Dahl rats in heart tissue was detected. Using Principal Component Analysis, Linear Discriminant Analysis and other statistical means we have established sets of differentially expressed proteins, candidates for further molecular analysis of the heart failure mechanisms.

Acquired Gerbode defect after endocarditis.

Fig. 2. Intra-operative view through the opened right atrium (A) and the aortotomy (B). There is a large defect at the base of the tricuspid septal leaflet (arrow) with vegetations (A). A surgical spatula within the defect (introduced from the right atrial side) demonstrates the communication (dashed arrow) to the left ventricle just below the right coronary to non-coronary commissure (B). RS, right coronary sinus.