Hemodynamics of the string phenomenon in the internal thoracic artery grafted to the left anterior descending artery with moderate stenosis.

PURPOSE: The internal thoracic artery is the choice of graft for coronary artery bypass grafting due to the excellent long-term patency. However internal thoracic artery graft failures still occur due to diffuse narrowing, known as the string phenomenon. Studies suggest that the string phenomenon is caused by competitive flow when the coronary stenosis is not serious, but the hemodynamics of the string phenomenon are still unclear. The purpose of this study is to clarify the hemodynamic characteristics of the string phenomenon. MATERIALS: A patient-specific 3-dimensional model of the aortic arch and coronary arteries was reconstructed. A moderate stenosis was applied to the left anterior descending artery. The internal thoracic artery was used to bypass the stenosis. Two further 3D models were built to study the hemodynamics of the string phenomenon. METHODS: A numerical study was performed by coupling the 3D artery model with 0-dimensional lumped parameter model of the cardiovascular system. RESULTS: The graft flow, native coronary flow, wall shear stress and oscillatory shear index were calculated and illustrated. Inverse flow and high oscillatory shear index appeared on the internal thoracic artery graft when the stenosis was moderate. CONCLUSION: High oscillatory shear index might be the major hemodynamic characteristic of the string phenomenon in internal thoracic artery graft. The inverse graft flow and the difference in graft flow caused by clamping the stenosis can be used to evaluate the probability of observing the string phenomenon.

Hemodynamic analysis of sequential graft from right coronary system to left coronary system.

BACKGROUND: Sequential and single grafting are two surgical procedures of coronary artery bypass grafting. However, it remains unclear if the sequential graft can be used between the right and left coronary artery system. The purpose of this paper is to clarify the possibility of right coronary artery system anastomosis to left coronary system. METHODS: A patient-specific 3D model was first reconstructed based on coronary computed tomography angiography (CCTA) images. Two different grafts, the normal multi-graft (Model 1) and the novel multi-graft (Model 2), were then implemented on this patient-specific model using virtual surgery techniques. In Model 1, the single graft was anastomosed to right coronary artery (RCA) and the sequential graft was adopted to anastomose left anterior descending (LAD) and left circumflex artery (LCX). While in Model 2, the single graft was anastomosed to LAD and the sequential graft was adopted to anastomose RCA and LCX. A zero-dimensional/three-dimensional (0D/3D) coupling method was used to realize the multi-scale simulation of both the pre-operative and two post-operative models. RESULTS: Flow rates in the coronary artery and grafts were obtained. The hemodynamic parameters were also showed, including wall shear stress (WSS) and oscillatory shear index (OSI). The area of low WSS and OSI in Model 1 was much less than that in Model 2. CONCLUSIONS: Model 1 shows optimistic hemodynamic modifications which may enhance the long-term patency of grafts. The anterior segments of sequential graft have better long-term patency than the posterior segments. With rational spatial position of the heart vessels, the last anastomosis of sequential graft should be connected to the main branch.

[Mutation analysis and prenatal diagnosis of FBN1 gene mutations for four patients with Marfan syndrome].

OBJECTIVE: To screen for mutations of fibrillin-1 (FBN1) gene in 4 patients with Marfan syndrome in order to provide prenatal diagnosis and genetic counseling. METHODS: Potential mutations of the FBN1 gene in the probands were detected with PCR and DNA sequencing. Subsequently, genomic DNA was extracted from amniotic fluid sampled between 18 to 20 weeks gestation. The mutations were confirmed with denaturing high-performance liquid chromatography - robust microsatellite instability (DHPLC-MSI) analysis with maternal DNA as reference. The products were further analyzed by direct sequencing and BLAST search of NCBI database. RESULTS: An IVS46+1G>A substitution was identified in patient A at +1 position of intron 46 of the FBN1 gene. Two novel missense mutations were respectively discovered at positions +4453 of intron 35 in patient B (Cys1485Gly) and position +2585 of intron 21 in patient C (Cys862Tyr). In patient D, a novel deletion (c.3536 delA) was found at position +3536 of intron 28. In all of the 4 cases, the same mutations have been identified in the fetuses. CONCLUSION: FBN1 gene analysis can provide accurate diagnosis of Marfan syndrome, which can facilitate both prenatal diagnosis and genetic counseling.

Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections.

Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-ß receptor-1 (TGFBR1) and transforming growth factor-ß receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.

Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice.

RATIONALE: A number of epidemiological studies have suggested an association of hyperhomocysteinemia (HHcy) and abdominal aortic aneurysm (AAA), but discrepancies exist. In addition, we lack direct evidence supporting a causal role. OBJECTIVE: We determined the association and contribution of HHcy to AAA formation. METHODS AND RESULTS: We first performed a meta-analysis of studies involving 1489 subjects and found a strong association of HHcy and AAA (odds ratio, 7.39). Next, we used angiotensin II-infused male apolipoprotein E-deficient mice and tested whether HHcy contributes to AAA pathogenesis. Homocysteine (Hcy) supplement (1.8 g/L) in drinking water resulted in mild HHcy. Intriguingly, HHcy greatly increased the incidence of angiotensin II-induced AAA and aortic dissection in apolipoprotein E-deficient mice (vehicle versus Hcy: 50% versus 100%; P<0.05). Histology indicated HHcy markedly exaggerated aortic adventitial inflammation. Increased levels of proinflammatory interleukin-6 and monocyte chemoattractant protein-1 were preferentially colocalized within adventitial fibroblasts in HHcy plus angiotensin II mice, which suggested the importance of adventitial fibroblasts activation in Hcy-aggravated AAA. Hcy sequentially stimulated adventitial fibroblasts transformation into myofibroblasts, secretion of interleukin-6 and monocyte chemoattractant protein-1, and consequent recruitment of monocytes/macrophages to adventitial fibroblasts, which was abolished by the NADPH oxidase inhibitor diphenyliodonium. NADPH oxidase 4, but not other homologs of NADPH oxidase, was significantly upregulated by Hcy in adventitial fibroblasts, whereas NADPH oxidase 4 small interfering RNA silencing diminished Hcy-induced adventitial fibroblasts activation. Finally, folic acid supplement (0.071 µg/g per day) markedly reduced HHcy-aggravated angiotensin II-induced AAA formation in apolipoprotein E-deficient mice. CONCLUSIONS: HHcy may aggravate AAA formation at least partially via activating adventitial fibroblast NADPH oxidase 4.

[Clinical outcome of mitral valve repair in primary infective endocarditis with mitral insufficiency].

OBJECTIVE: To study the clinical results of mitral valve repair in patients of primary infective endocarditis with mitral insufficiency. METHODS: From January 2004 to July 2007, 40 patients who had undergone valve repair procedure for infective endocarditis with mitral insufficiency were analyzed retrospectively. There were 26 male and 14 female patients, with an average age of (34.0 +/- 3.5) years old, including 6 patients of underlying heart disease, 34 patients of no previously underlying heart disease. There were 12 patients in NYHA functional class II, 19 patients in class III, 9 patients in class IV preoperatively. Preoperative echocardiography showed moderate to severe MR in all patients. The surgery was performed under extracorporeal circulation and moderate hypothermia. The distribution of anatomical lesion according to surgical findings were vegetation in 32 patients, leaflet prolapsed in 34 patients, leaflet perforation in 16 patients, chordal rupture in 32 patients, and annular abscess in 2 patients. The vegetations and infected tissues were debrided. The surgery consisted of complex methods to repair mitral valve, including direction leaflet closure in 5 patients, pericardial patch closure of leaflet perforation in 18 patients, chords reimplantation in 4 patients and chords transference in 6 patients, quadrangular resection in 12 patients, double orifice method in 17, closure of the commissure in 8, rings annuloplasty in 28 cases, and so on. There were 28 selective surgeries and 12 emergent ones. Patients were evaluated for early and long-term clinic and echocardiographic outcome before and after operation. RESULTS: There were no early postoperative death. Mitral valve repair was feasible in 39 patients, one patient was transformed to mitral valve replacement during the operation. Postoperative echocardiography demonstrated no (n = 24) or mild (n = 15) mitral regurgitation at the discharge examination and observed significant reductions in left ventricular end diastolic [from (62 +/- 7) mm to (51 +/- 6) mm, P < 0.05] and end systolic dimensions [from (45 +/- 3) mm to (40 +/- 4) mm, P < 0.05] and left atrial dimensions [from (49 +/- 4) mm to (42 +/- 6) mm, P < 0.05]. Mean follow-up (25.6 +/- 3.2) months, freedom from recurrent moderate to severe MR, freedom from repeat operation or infective endocarditis, revealed patients were 36 cases in NYHY class I, 3 cases in class II. CONCLUSION: Mitral valve repair for mitral valve endocarditis is feasible with a satisfied clinical outcome, maintains valve competency with significant reductions in left atrial and left ventricular dimensions after surgery.

[Clinical analysis of pregnancy and postpartum cardiovascular complications in Marfan syndrome].

OBJECTIVE: To investigate the management of pregnancy and cardiovascular complications in women with Marfan syndrome (MFS). METHODS: From October 1994 to September 2006, 30 patients with MFS undergoing cardiovascular surgery were studied retrospectively. RESULTS: In the labor of 46 offsprings given birth by 30 women, 5 cases (11%) were performed elective cesarean section because of the existence of aortic complication, and 12 (26%) were diagnosed as MFS. The gestation in two patients was terminated due to deterioration of aortic abnormalities during their third trimester, and they received surgical treatment with Bentall procedure. Two developed acute aortic dissection during labor and post delivery respectively. With the manipulation of anticoagulation peripartum, one who had the implantation with mechanical prosthesis went through pregnancy and delivery uneventfully. The average duration between delivery and cardiovascular surgery was (15 +/- 9) years. CONCLUSIONS: Vaginal delivery can be done safely in patients with the MFS who do not have or have mild cardiovascular system abnormalities, aortic dissection, or other important cardiac abnormalities, cesarean section should be the preferred method of delivery. Women with MFS are at increased risk for dissection and congestive heart failure during pregnancy and should be counseled before pregnancy about these risks, as well as the inheritance of the condition.

Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction.

Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardiomyoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were pre-prepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the perii-nfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.

Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure.

We hypothesized that chronic xanthine oxidase inhibition (XOI) would have favorable effects on both ventricular and vascular performance in evolving heart failure (HF), thereby preserving ventricular-vascular coupling. In HF, XOI reduces oxidative stress and improves both vascular and myocardial function. Dogs were randomized to receive either allopurinol (100 mg/day p.o.) or placebo following surgical instrumentation for chronic measurement of left-ventricular pressure and dimension and during induction of HF by rapid pacing. In the placebo group (n = 8), HF was characterized by increased LV end-diastolic pressure (LVEDP, 10.2 +/- 5.5 and 29.8 +/- 3.9 mmHg, before and after HF, respectively, P < 0.05), end-diastolic dimension (LVEDD, from 29.5 +/- 3.2 to 34.3 +/- 3.2 mm, P < 0.001), and afterload (arterial elastance, Ea, from 17.9 +/- 1.2 to 42.6 +/- 7.9 mmHg/mm, P < 0.05), and reduced contractility (End-systolic ventricular elastance, Ees, from 10.8 +/- 1.3 to 5.6 +/- 2.3 mmHg/mm, P < 0.05). Thus, ventricular-vascular coupling (Ees/Ea ratio) fell 57.6+/-9% (0.61 +/- 0.1 to 0.16 +/- 0.1, P < 0.05). Allopurinol (n = 9) profoundly attenuated both the Ea increase (from 22.3 +/- 3 to 25.6 +/- 4.6 mmHg/mm, P = NS) and the fall in Ees (from 11.8+/-1.1 to 11.7+/-1, P = NS), thereby preserving the Ees/Ea ratio (from 0.58 +/- 0.1 to 0.56 +/- 0.1, P < 0.001 vs. placebo). Allopurinol did not affect the increase in preload (LVEDP and LVEDD). XO cardiac mRNA and protein were similarly upregulated approximately fourfold in both groups. Allopurinol ameliorates increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular-vascular coupling. These results demonstrate a unique and potent hemodynamic profile of XOI, thereby providing further rationale for developing XOIs as a novel HF therapy.

Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart.

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.