Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome.

BACKGROUND: Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined. METHODS: Ten consecutive BAV patients [8 men, age range 24-42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients. RESULTS: We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype. CONCLUSIONS: The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing.

Prognostic value of Doppler-derived mitral deceleration time on left ventricular reverse remodelling after undersized mitral annuloplasty.

AIMS: This study was aimed at exploring the predictive value of Doppler-Derived Mitral Deceleration Time (DT) on left ventricular reverse remodelling (LVRR) in patients with chronic ischaemic mitral regurgitation (CIMR) undergoing combined undersized mitral annuloplasty (UMRA) and coronary artery bypass grafting (CABG). METHODS AND RESULTS: Two hundred and fifteen patients undergoing combined UMRA and CABG for CIMR between September 2001 and September 2007 in our Institution were divided into four groups on the basis of baseline DT: Group 1, normal (n = 48), Group 2, impaired relaxation (n = 61), Group 3, pseudonormal (n = 50), and Group 4, restrictive (n = 56). Echocardiograms were performed, pre-operatively, at discharge and at follow-up appointments (100% complete, early, median 6 months [interquartile range 4-8 months]) and late, median 38 months (17-61 months). Left ventricular reverse remodelling, defined as a reduction in ESV > 15%, occurred in 95.7, 96.3, 88.3, and 0% in Groups 1, 2, 3, and 4, respectively (P < 0.001). Logistic regression analysis showed that DT

Echo/Doppler-derived time intervals are able to predict left ventricular reverse remodeling after cardiac resynchronization therapy.

AIM: We evaluated the predictive value of echo/Doppler derived indices, which reflect the duration of the isovolumic phases of the cardiac cycle, in identifying cardiac resynchronization therapy (CRT) responders. METHODS AND RESULTS: In 105 patients before and 6 months after CRT the following echo/Doppler parameters were evaluated: myocardial performance index (MPI) as the sum of isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) divided by ejection time; total isovolumic time (t-IVT) as the sum of IVCT and IVRT divided by the RR interval; and standard deviation of the time to systolic peak velocity (Ts-SD) as asynchrony index. After 6 months, patients were defined responders according to 15% left ventricle (LV) end-systolic volume reduction or more. At baseline, responders (53.3%) had higher t-IVT and MPI than nonresponders (0.30 +/- 0.06 versus 0.22 +/- 0.05, P < 0.0001 and 1.01 +/- 0.27 versus 0.73 +/- 0.19, P < 0.0001, respectively). Receiving operating characteristic curve analysis showed that both t-IVT (80.3% sensitivity and 83.7% specificity, cut-off = 0.263) and MPI (78.6% sensitivity and 81.6% specificity, cut-off = 0.84) could predict CRT response. Baseline t-IVT correlated well to end-systolic volume reduction (r = -0.56, P < 0.00001). CONCLUSION: Echo/Doppler derived indices, describing physiologic abnormalities of the isovolumic contraction and relaxation phase, are able to predict CRT-induced reverse remodeling.

Left ventricular diastolic function after restrictive mitral ring annuloplasty in chronic ischemic mitral regurgitation and its predictive value on outcome and recurrence of regurgitation.

BACKGROUND: This study was aimed at exploring the predictive value of diastolic function on clinical outcome and recurrence of ischemic mitral regurgitation following combined undersized mitral annuloplasty (UMRA) and coronary artery bypass grafting (CABG). METHODS: Two hundred-thirty-four patients with chronic ischemic mitral regurgitation (CIMR) who survived combined UMRA and CABG between September 2001 and September 2007, were divided into four groups on the basis of baseline deceleration time (DT) and systolic-diastolic pulmonary venous flow ratio (S/D): Group 1, normal (n=48), Group 2, impaired relaxation (n=61), Group 3, pseudonormal (n=60) and Group 4, restrictive (n=65). Echocardiograms were performed, preoperatively, at discharge and at follow-up appointments (early, 6 months [interquartile range, IQR] 3-8 months; late, 38 months [IQR17-53 months]). RESULTS: Early mortality rate was highest in the restrictive group (9.2%, p<0.001). In addition 6-year actuarial survival was significantly lower in Group 4 (p=0.025). At late follow-up, among patients in Group 4, 58.4% (n=38) had an MR grade >or=2 (p<0.001). Furthermore, DT<140 ms and S/D<0.80 were independent predictors of early (p<0.001 and 0.004, respectively) and late (both p<0.001) death. Finally DT<140 ms was the only diastolic independent predictor of MR recurrence (p<0.001). CONCLUSIONS: In patients with CIMR undergoing combined CABG and UMRA restrictive LV diastolic filling pattern is an important preoperative marker of high early and late death and recurrence of MR.

AGT and ACE genes influence classic mitral valve prolapse predisposition in Marfan patients.

BACKGROUND: In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen (AGT) M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients. METHODS: We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis. RESULTS: The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one (p=0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p=0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse (OR 3.02, p=0.016). CONCLUSIONS: Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.

Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.

In the post-infarcted heart, grafting of precursor cells may partially restore heart function but the improvement is modest and the mechanisms involved remain to be elucidated. Here, we explored this issue by transplanting C2C12 myoblasts, genetically engineered to express enhanced green fluorescent protein (eGFP) or eGFP and the cardiotropic hormone relaxin (RLX) through coronary venous route to swine with experimental chronic myocardial infarction. The rationale was to deliver constant, biologically effective levels of RLX at the site of cell engraftment. One month after engraftment, histological analysis showed that C2C12 myoblasts selectively settled in the ischaemic scar and were located around blood vessels showing an activated endothelium (ICAM-1-,VCAM-positive). C2C12 myoblasts did not trans-differentiate towards a cardiac phenotype, but did induce extracellular matrix remodelling by the secretion of matrix metalloproteases (MMP) and increase microvessel density through the expression of vascular endothelial growth factor (VEGF). Relaxin-producing C2C12 myoblasts displayed greater efficacy to engraft the post-ischaemic scar and to induce extracellular matrix re-modelling and angiogenesis as compared with the control cells. By echocardiography, C2C12-engrafted swine showed improved heart contractility compared with the ungrafted controls, especially those producing RLX. We suggest that the beneficial effects of myoblast grafting on cardiac function are primarily dependent on the paracrine effects of transplanted cells on extracellular matrix remodelling and vascularization. The combined treatment with myoblast transplantation and local RLX production may be helpful in preventing deleterious cardiac remodelling and may hold therapeutic possibility for post-infarcted patients.