Differing patterns of matrix metalloproteinase expression in patients with ascending aortic aneurysms and bicuspid aortic valves

Purpose: Abnormal matrix metalloproteinase (MMP) expression contributes to the development of infrarenal abdominal aortic aneurysms. Recent data have suggested that MMP-2 and MMP-9 may also play a role in thoracic aortic disease. We sought to determine whether the presence of a bicuspid aortic valve (BAV) had an impact on the pattern of MMP expression in ascending aortic aneurysms. Methods: Intraoperative samples of ascending aorta were obtained from 19 patients with ascending aortic aneurysms, 8 (42%) of which also had a BAV. Control samples of ascending aorta were obtained from 6 patients undergoing coronary artery bypass or organ donation/transplantation. None of the patients had aortic dissection or Marfan syndrome. Immunohistochemistry was used to identify expression of MMP-2 and MMP-9 within the aortic wall. Results: The frequency of MMP-2 expression did not differ between BAV patients (5/8, 63%) and non-BAV aneurysm patients (9/11, 82%; p = 0.6); MMP-2 expression was absent in the control group (0/6; p = 0.03 vs. BAV and 0.002 vs. non-BAV). MMP-9 expression, however, occurred rarely in both the BAV groups (1/8, 13%) and the control group (1/6, 17%; p = 1.0); positive MMP-9 staining was substantially more common in the non-BAV patients (7/11, 64%) than in the BAV group (p = 0.06). Conclusions: Ascending aortic aneurysms are associated with increased MMP-2 expression, regardless of the presence of a BAV. Increased MMP-9 expression, however, primarily occurred in aneurysms without a BAV. Variations in MMP expression patterns among different types of thoracic aortic aneurysms warrant further investigation.     

C-reactive protein as a marker of severe calcification among patients with bicuspid aortic valve disease

Background. Bicuspid aortic valve (BAV) may be associated with aneurysmal dilatation of the ascending aorta, even after successful aortic valve replacement. There are as yet no biomarkers that correlate with the progression of such disease. Elevated levels of C-reactive protein (CRP), a marker of acute inflammation, are seen in chronic rheumatic valve disease, especially those with multivalvular disease, and have been shown to return to normal after valve replacement. We hypothesized that dilatation of the ascending aorta with BAV would be associated with ongoing inflammation, and, accordingly, elevated levels of CRP. Methods. High-sensitivity CRP levels [normal 0.02-0.8 mg/dl] were assayed from blood samples drawn in the operating room prior to cardiopulmonary bypass in 25 patients (4 female and 21 male, mean age 50 years, range 18-72 years) with bicuspid aortic valve disease undergoing valve replacement or repair. Preoperative cardiovascular risk factors for coronary artery disease, as well as valve function, area, and ascending aortic diameter based on echocardiogram were noted. Degree of valve calcification (none to minimal or moderate to severe) was recorded based on surgical observation or pathology report. None of the patients had active infections, tumors, or acute myocardial infarction. Results. There was no correlation of the CRP level to aortic diameter, valve area, patient age, gender, or body mass index (BMI). CRP levels were higher among patients with moderate-to-severe valvular calcification (n = 13, mean 0.711 ± 2.22 mg/dl) compared with none or minimal valvular calcification (n = 12, mean CRP 3.071 ± 5.62 mg/dl) (P = 0.0065). This difference remained statistically significant after excluding patients with coronary artery disease (n = 13). There was a trend for higher CRP level among patients with aortic stenosis (mean CRP 5.378 mg/dl) compared to those with aortic regurgitation (mean CRP 0.103 mg/dl) (P = 0.058). Conclusions. Elevated CRP among patients with BAV did not correlate with aortic diameter, but was associated with advanced calcific valve disease. This assay may prove useful in understanding the pathogenesis of calcification in this group of patients and to identify those with BAV at risk for progressive aortic valve disease.     

Long-term outcomes after ascending aortic replacement and aortic root replacement for type A aortic dissection

 Open in a separate windowOBJECTIVESWe investigated whether the selective use of supracoronary ascending aorta replacement achieves late outcomes comparable to those of aortic root replacement for acute Stanford type A aortic dissection (TAAD).METHODSPatients who underwent surgery for acute type A aortic dissection from 2005 to 2018 at the Helsinki University Hospital, Finland, were included in this analysis. Late mortality was evaluated with the Kaplan–Meier method and proximal aortic reoperation, i.e. operation on the aortic root or aortic valve, with the competing risk method.RESULTSOut of 309 patients, 216 underwent supracoronary ascending aortic replacement and 93 had aortic root replacement. At 10 years, mortality was 33.8% after aortic root replacement and 35.2% after ascending aortic replacement (P = 0.806, adjusted hazard ratio 1.25, 95% confidence interval, 0.77–2.02), and the cumulative incidence of proximal aortic reoperation was 6.0% in the aortic root replacement group and 6.2% in the ascending aortic replacement group (P = 0.65; adjusted subdistributional hazard ratio 0.53, 95% confidence interval 0.15–1.89). Among 71 propensity score matched pairs, 10-year survival was 34.4% after aortic root replacement and 36.2% after ascending aortic replacement surgery (P = 0.70). Cumulative incidence of proximal aortic reoperation was 7.0% after aortic root replacement and 13.0% after ascending aortic replacement surgery (P = 0.22). Among 102 patients with complete imaging data [mean follow-up, 4.7 (3.2) years], the estimated growth rate of the aortic root diameter was 0.22 mm/year, that of its area 7.19 mm²/year and that of its perimeter 0.43 mm/year.CONCLUSIONSWhen stringent selection criteria were used to determine the extent of proximal aortic reconstruction, aortic root replacement and ascending aortic replacement for type A aortic dissection achieved comparable clinical outcomes.     

Decision-making algorithm for ascending aortic aneurysm: Effectiveness in clinical application?

Objective

The risk of rupture and dissection in ascending thoracic aortic aneurysms increases as the aortic diameter exceeds 5 cm. This study evaluates the clinical effectiveness of a specific algorithm based on size and symptoms for preemptive surgery to prevent complications.

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Background. Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. The concomitant production of proinflammatory mediators by the pulmonary artery itself may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC) mediated mechanism. Methods. Isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia (95% N₂/5% CO₂, pO₂ = 30-35 mmHg) in the presence and absence of the protein kinase C inhibitor chelerythrine (1 μmol/L). Following 60 min of hypoxia, pulmonary artery rings were subjected to mRNA analysis for TNF-μ, IL-1β, and iNOS via RT-PCR. Data were analyzed using two-way analysis of variance (ANOVA) with post-hoc Bonferonni test or unpaired t tests with alpha level less than 0.05 considered statistically significant. Results. Hypoxia caused a biphasic contraction: an early and delayed contraction which occurred 1-3 and 15-20 min, respectively, after the onset of hypoxia. Hypoxic pulmonary artery tissue had increased expression of TNF-μ, IL-1β, and iNOS mRNA compared to normoxic controls. PKC inhibition significantly (P < 0.001) attenuated delayed hypoxic contraction (61.55 ± 3.91% versus 94.07 ± 5.94% in hypoxia alone) and prevented hypoxia-induced pulmonary artery tissue expression of TNF-μ, IL-1β, and iNOS mRNA. Conclusions. These findings demonstrate that hypoxia results in pulmonary artery contraction and promotes the expression of inflammatory mediators. Both processes are mediated by PKC. We conclude that there may be a therapeutic role for PKC inhibition in the treatment of acute hypoxic pulmonary vasoconstriction.     

Aortic size in acute type A dissection: implications for preventive ascending aortic replacement

Objective: Elective ascending aortic replacement is recommended to prevent acute type A aortic dissection when any segment of the proximal aorta is greater than 5.5 cm. However, little data exist that meticulously describe the size of the ascending aorta at multiple levels in patients who suffer acute type A dissections. We sought to definitively characterize the size distribution of the proximal aorta in this patient population. Methods: Preoperative transesophageal echocardiography was used to measure the diameter of the proximal aorta at the aortic annulus, in the sinus segment, at the sinotubular junction and in the ascending aorta in 177 non-Marfan patients with tricuspid aortic valves who presented to one institution over a 10-year period with an acute type A dissection. Predicted aortic diameters for each patient based on the individual's age, gender and body size were also calculated at all four aortic positions using previously published regression equations derived from a large cohort of normal patients. Results: Sixty patients were female (33.9%; aged 67 ± 12 years) and 117 were male (66.1%; aged 60 ± 17 years). Sixty-two percent of all patients had maximum aortic diameters less than 5.5 cm at time of dissection and 42% of patients had maximum aortic diameters less than 5.0 cm. Over 20% of all patients had maximal aortic dimensions of less than 4.5 cm. In women, 12% of the dissected aortas had a maximal dimension less than 4.0 cm. Conclusions: The majority of patients with acute type A aortic dissection present with aortic diameters <5.5 cm and thus do not fall within current guidelines for elective ascending aortic replacement. Methods other than size measurement of the ascending aorta are needed to identify patients at risk for dissection. Aggressive medical management of patients with ascending aortic diameters over 4 cm is warranted. Preventative replacement of the ascending aorta at 4.5 cm should be considered especially at high volume aortic surgery centers and patients having cardiac surgery for other indications.     

Safety and efficacy of ascending aorta cannulation during repair of acute type A aortic dissection (PA29-04): “Presented at the 65th Annual Scientific Meeting of the Japanese Association for Thoracic Surgery”

Objective

Antegrade central perfusion for acute Stanford type A aortic dissection prevents malperfusion and retrograde cerebral embolism during cardiopulmonary bypass. Prompt establishment of antegrade perfusion via the ascending aorta may improve surgical results of type A dissections, especially in situations of hemodynamic instability. Thus, we evaluated the safety and efficacy of cannulation of the dissected ascending aorta in acute type A dissection.

Methods

We reviewed the medical charts of patients undergoing repair of acute ascending aortic dissection (n = 52) from April 2010 to April 2013. Cannulation was accomplished in 29 patients via the ascending aorta (central) and in 23 patients via the femoral or axillary artery (peripheral). The ascending aorta was routinely cannulated using Seldinger technique under epiaortic ultrasound guidance. Comorbidities, mortality, complications, and durations of hospital stays were compared for the groups.

Results

In all cases, routine cannulation of the ascending aorta was safely performed with no resultant malperfusion or thromboembolism. Mean operative duration, cardiopulmonary bypass time, intubation time, and intensive care unit stay were significantly shorter in the central group. Two patients (6.8 %) in the central group died compared with four patients (17.3 %) in the peripheral group (P = 0.005).

Conclusions

Antegrade central perfusion via the ascending aorta, a simple and safe technique that enables rapid establishment of antegrade systemic perfusion, was as safe as peripheral cannulation in patients with type A acute aortic dissection.     

Nitrofen inhibition of pulmonary growth and development occurs in the early embryonic mouse

Background/Purpose: It was believed previously that pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) was a consequence of the herniation of abdominal viscera into the chest. Using the murine nitrofen-induced model of CDH, the authors evaluated lung growth and development before diaphragm closure or herniation. Methods: The authors examined nitrofen-exposed early embryonic lungs on embryonic day 12 (E12). Branching morphogenesis was quantified before and after 4 days in culture in serumless chemically defined media and compared with age-matched control lungs. The mRNA expression of proliferative and developmental markers in cultured lungs was then determined. Results: Nitrofen-exposed lungs had 30% fewer total terminal branches than age-matched controls (9.3 [plusmn] 1.9 nitrofen v 13.7 [plusmn] 2.6 control; P [lt ] .001). Hypoplasia also was more profound in the left than the right lung. These effects persisted after culturing the lungs for 4 days in serumless chemically-defined media (31.7 [plusmn] 6.8 nitrofen v 42.9 [plusmn] 8.4 control, P [lt ] .001). Furthermore, the mRNA expression of proliferative and developmental markers was decreased in nitrofen-exposed E12 lungs cultured for 4 days (as a percentage of age-matched controls): cyclin A (69.28%; P = .04), Nkx2.1 (44.4%, 0.04), SP-A (24.1%; P = .008), SP-B (23.4%; P = .05), SP-C (20%; P = .06), and CC-10 (13.8%; P = .04). Conclusion: Nitrofen induces primary pulmonary hypoplasia and immaturity in the early embryonic mouse, and this effect persists in culture. J Pediatr Surg 37:1263-1268.     

Natural history of the proximal aorta in patients with descending thoracic aortic disease

Objective

This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease.

Comparative study of brain protection in ascending aorta replacement for acute type A aortic dissection: retrograde cerebral perfusion versus selective antegrade cerebral perfusion

Objectives

Postoperative disorders of the central nervous system remain a major problem in thoracic aortic surgery. Both retrograde cerebral perfusion and selective antegrade cerebral perfusion have become established techniques for cerebral circulatory management. In this study, we compared neurologic outcomes and mortality between retrograde cerebral perfusion and antegrade selective cerebral perfusion in patients with acute type A aortic dissection who underwent emergency ascending aorta replacement.

Methods

Between January 2003 and April 2011, a total of 203 patients with acute type A aortic dissection underwent emergency ascending aorta replacement in our hospital. We performed retrograde cerebral perfusion in 109 patients before 2006, and then mainly performed antegrade selective cerebral perfusion in 94 patients from 2006 onward.

Results

Cardiopulmonary bypass time and systemic circulatory arrest time were significantly longer in the antegrade selective cerebral perfusion group (p?=?0.04, p?<?0.001, respectively). The incidences of transient brain dysfunction and permanent brain dysfunction after surgery did not differ significantly between the groups. There were also no differences between the groups in other intraoperative variables, such as aortic cross-clamp time and the lowest rectal temperature, or in operative outcomes, including postoperative intensive-care-unit stay, mean peak amylase, and lipase levels until postoperative day 7, and 30-day mortality.

Conclusion

Both retrograde cerebral perfusion and antegrade selective cerebral perfusion were associated with acceptable levels of postoperative neurologic deficits, mortality, and morbidity. Either of these techniques for brain protection can be used selectively, based on a comprehensive assessment of general condition, in patients undergoing surgery for acute type A aortic dissection.     

A canine model of multiple organ dysfunction following acute type-A aortic dissection

Purpose

Despite recent advances in surgical techniques and perioperative management, the mortality rate in patients with type-A aortic dissection remains high. The establishment of an animal model that exhibits the clinical features of acute aortic dissection would facilitate investigations of the pathogenesis of aortic dissection and the development of appropriate treatments.

Methods

Twelve beagle dogs were divided into two groups: (1) an experimental group treated with the modified surgical procedure to generate an ascending aortic dissection (n?=?6); and (2) a control group treated with a median sternotomy but without aortic dissection. All animals received continuous intravenous infusion of adrenaline to achieve controlled hypertension. The tearing length of the aortic intima, the pathological changes, the plasma levels of inflammatory mediators, and the organ functions were dynamically examined and compared.

Results

The modified surgical procedure plus controlled hypertension successfully established a novel canine model of acute type-A aortic dissection. In the experimental group, the tearing length of the aortic intima reached the abdominal aorta (average 17?cm), and a false lumen was formed in the aortic media. The lung and intestinal tract had obvious structural injuries. The plasma levels of all inflammatory mediators tested, including tumor necrosis factor-α, interleukin-6, interleukin-10, and endotoxin, were significantly higher in the experimental animals than in the control group. The functional examination of the liver and kidneys revealed substantial disturbances, as reflected by the elevated plasma levels of alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen in the experimental group.

Conclusions

A novel canine model of acute Stanford type-A aortic dissection has been developed, which showed multiple organ dysfunction that mimicked the clinically relevant features observed in man. This aortic dissection model is unique, and may further improve our understanding of the underlying pathogenesis of aortic dissections.     

Surgical treatment of acute arch dissection

Objectives: Acute type A arch dissections are rare and no consensus has been reached on their surgical treatment. We studied perioperative risk factors for mortality in arch dissection patients.Methods: Between October 1995 and October 2001, 108 patients with acute type A dissection were operated on, of whom 16 had acute arch dissections. Their mean age was 58±9 (44–77). Surgery involved total arch replacement in 4, hemiarch replacement in 10, and intimal tear repair with pledgeted sutures and ascending aortic replacement in 2.Results: One patient who underwent total arch replacement died intraoperatively due to bleeding. Both patients who underwent ascending aortic replacement and primary repair of arch tears died 2 days postoperatively, 1 due to bleeding, and the other due to multiorgan failure. In-hospital mortality was thus 18.75%, or 3 of 16. All 3 had cardiac tamponade preoperatively. The 13 survivors were discharged after a mean hospital stay of 11±6 days. Mean follow-up was 38±25 months, from 3 months to 6 years. One patient died due to graft infection 3 months postoperatively, but the remaining 12 remain in good condition. Univariate predictors of in-hospital mortality were the type of surgery (primary intimal tear repair) (p=0.027) and preoperative cardiac tamponade (p=0.007).Conclusion: Surgical treatment of acute type A-arch dissections can be done with reasonable mortality and mid-term survival comparable with those of other subgroups with acute type A dissection. As with series of arch dissections, our patient population is too small to draw specific conclusions, but our experience leads us to conclude that the sites of intimal tears should be resected in acute type A arch dissection.     

Murine nitrofen-induced pulmonary hypoplasia does not involve induction of TGF-beta signaling

Background/Purpose: In the murine nitrofen-induced model of congenital diaphragmatic hernia (CDH), the lungs are primarily hypoplastic and immature even before diaphragmatic closure. Because excess transforming growth factor-[beta ] (TGF-[beta ]) signaling induces pulmonary hypoplasia, the authors hypothesized that primary hypoplasia after nitrofen exposure may be caused by abberant signaling by the TGF-[beta ] pathway. Therefore, abrogation of TGF-[beta ] signaling might rescue the hypoplasia. Methods: The authors performed intratracheal microinjections of a recombinant adenoviral vector encoding a dominant-negative TGF-[beta ] type II receptor (AdIIR-DN) in nitrofen-exposed and control E12 mouse lungs, which then were cultured for 4 days in serumless chemically defined media. The mRNA expression of Smad2, 3, 4, and 7 in nitrofen-exposed and control E12 lungs after 4 days in culture were compared. Results: ADIIR-DN increased terminal branching in control lungs by 28% compared with lungs injected with control virus (61.8 [plusmn] 4.6 v. 48.4 [plusmn] 4.7, P = .004). However, there was no difference between nitrofen-exposed lungs injected with ADIIR-DN and those injected with control virus. Compared with control lungs, Smad mRNA expression was decreased markedly in nitrofen-exposed lungs: Smad2 (40%, P = .16), Smad3 (29%, P = .02), Smad4 (25%, P = .07), and Smad7 (36%, P = .04). Conclusions: Because abrogation of TGF-[beta ] signaling does not rescue the hypoplasia seen in the nitrofen model, and Smad expression is decreased in nitrofen-exposed lungs, the TGF-[beta ] pathway does not appear to play a role in nitrofen-induced pulmonary hypoplasia. J Pediatr Surg 37:1123-1127.     

Clinical outcomes after separate and composite replacement of the aortic valve and ascending aorta

Objectives

We sought to compare the clinical profile and outcomes of operations for aortic valve disease and ascending aortic aneurysm in patients treated with aortic valve replacement and supracoronary replacement of the ascending aorta or composite replacement of the aortic valve and ascending aorta (Bentall operation).

Methods

From 1990 through 2001, 133 patients had aortic valve replacement and supracoronary replacement of the ascending aorta, and 452 patients had Bentall operations. Aortic valve replacement and supracoronary replacement of the ascending aorta was performed in patients who had aortic valve disease and dilation of the ascending aorta, whereas the Bentall operation was performed in patients with aortic root abnormality and ascending aortic aneurysm. Mean follow-up was 4.6 ± 3.1 years and was 100% complete.

Results

Patients who had aortic valve replacement and supracoronary replacement of the ascending aorta were older (61 ± 13 vs 52 ± 16 years, P < .001) and more likely to have aortic stenosis, coronary artery disease, and mitral valve disease than those who had Bentall operations. The use of mechanical valves was equal in both groups (42% for aortic valve replacement and supracoronary replacement of the ascending aorta and 43% for the Bentall operation). Operative mortality was 5% for patients undergoing aortic valve replacement and supracoronary replacement of the ascending aorta and 4% for patients undergoing the Bentall operation (P = .45). Survival at 10 years was 57% ± 8% for patients undergoing aortic valve replacement and supracoronary replacement of the ascending aorta and 74% ± 4% for patients undergoing the Bentall operation (P = .04), but the type of operation had no effect on survival. Older age, moderate or severe left ventricular dysfunction, active endocarditis, previous cardiac surgery, and coronary artery disease were independent predictors of death. The freedom from reoperation at 10 years was 95% ± 5% for patients undergoing aortic valve replacement and supracoronary replacement of the ascending aorta and 94% ± 3% for patients undergoing the Bentall operation (P = .18). Reoperations were mostly because of tissue valve failure or endocarditis. The risk of valve-related complications was the same in both groups. No patient required reoperation for aortic root aneurysm after having aortic valve replacement and supracoronary replacement of the ascending aorta.

Conclusions

Aortic valve replacement and supracoronary replacement of the ascending aorta and the Bentall operation provide comparable long-term results. The Bentall operation is more appropriate for patients with aortic root abnormality and a dilated ascending aorta, whereas aortic valve replacement and supracoronary replacement of the ascending aorta is a perfectly acceptable operation for patients with aortic valve disease, normal or mildly dilated aortic sinuses, and a dilated ascending aorta.     

The role of ascending aortic size in outcomes of patients with uncomplicated acute type B aortic dissection

Objective

Recent studies demonstrate that uncomplicated acute type B aortic dissection (uATBAD) patients with enlarged descending thoracic aortic diameters are at high risk for development of complications. This study aimed to determine the association of maximum ascending aortic diameter and area and outcomes in patients with uATBAD.

Epidemiology and management of thoracic aortic dissections and thoracic aortic aneurysms in Ontario,Canada: A population-based study

Objectives

To determine hospital incidence, mortality, and management for thoracic aortic dissections and aneurysms.

Early aortic growth in acute descending aortic dissection

Open in a separate window OBJECTIVESAcute aortic dissection leads to the destabilization of the aortic wall, followed by an immediate increase in aortic diameter. It remains unclear how the aortic diameter changes during the dissection’s acute and subacute phases. The aim of this study was to evaluate the change in aortic geometry within 30 days after the onset of a descending aortic dissection.METHODSPatients with acute type B and non-A non-B dissection who had at least 2 computed tomography angiography scans obtained within 30 days after the onset of dissection were evaluated. Exclusion criteria were a thrombosed false lumen, connective tissue disorders and endovascular or open aortic repair performed prior to the second computed tomography angiography.RESULTSAmong 190 patients with acute aortic dissection, 42 patients met our inclusion criteria. Their aortic geometry was analysed according to the computed tomography angiography scans obtained between 0–3 (N = 35), 4–7 (N = 9) and 8–30 (N = 12) days after the dissection onset. The highest aortic diameter growth rate was observed in the first quartile of the thoracic aorta and measured 0.66 (0.06; 1.03), 0.29 (−0.01; 0.41) and 0.06 (−0.13; 0.26) mm/day at 0–3, 4–7 and 8–30 days after the dissection, respectively. Proximal entry location (P = 0.037) and entry located at the arch concavity (P = 0.008) were associated with a higher aortic diameter increase.CONCLUSIONSEarly rapid growth occurs during the first week after the descending aortic dissection—most intensely over the first 3 days, and this is associated with the location of the dissection’s entry.