MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach.

A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.

Na+ channel blockers vs class III antiarrhythmic drugs in treating sustained ventricular tachycardia: reversing and preventing as different electrophysiological mechanisms.

METHODS: 169 selected patients with previous AMI and inducible sustained ventricular tachycardia (sVT) at electrophysiological study (EPS) were followed-up prospectively for recurrent sVT during a five year period. At EPS, ventricular effective refractory period (VERP)/action potential duration (APd) ratio, ventricular conduction velocity, excitable gap, cycle length and QRS duration were measured. The patients with inducible sVT at basic programmed stimulation or after isoproterenol infusion (200 micrograms i.v.) underwent drug suppression tests (amiodarone, procamide, propanolol + procamide, amiodarone + propaphenone). On this basis, they were later assigned to 3 different groups: the amiodarone-treated group (n = 112), the procamide-treated group (n = 22) and the nonresponder group (control group, n = 35). RESULTS: After procamide infusion (100 mg/min for 10 min), at fast pacing drive the VERP/APd ratio was significantly increased from baseline levels (p < 0.001), the conduction velocity (Vmax) was significantly depressed (by 25%, p < 0.005), the excitable gap was significantly reduced (p < 0.005, 23% of cycle length) and 71 patients were no longer inducible; during sinus rhythm, Vmax was significantly reduced from baseline values (by 14%, p < 0.05), VERP was only moderately increased and the excitable gap was slightly but significantly prolonged (p < 0.01, 53% of cycle length): 147 patients were still inducible, without significant difference from baseline values. After amiodarone infusion (300 mg/100 ml i.v. over 10 min), Vmax was significantly reduced from baseline levels at fast pacing drive (by 21%, p < 0.001), while the excitable gap did not reduce significantly (34%) from baseline levels and 91 patients were still inducible; during sinus rhythm, conduction velocity was moderately depressed (by 7%, p < 0.05), while VERP was significantly increased from baseline levels (p < 0.002) and the excitable gap was significantly reduced (p < 0.001, 29% of cycle length); only 35 patients were still inducible. In the remaining 134 patients the reset curve showed excitable gaps = 24 +/- 3% of the cycle length. The absolute and relative values of the excitable gap measured in the 35 patients who were still inducible were significantly higher than those measured in patients no longer inducible (p < 0.05). At follow-up, the sVT recurrence rate was: 28% in the amiodarone-treated group, 43% in the procamide-treated group and 36% in the control group: control data were significantly different from the former (p < 0.05) but not from the latter group. Significant correlation was reported between the plasmatic concentration of procamide and amiodarone and the percentage of reduction of Vmax at fast pacing drive (r = 0.79, p < 0.05; r = 0.83, p < 0.01). Resulting variability checked by the analysis of variance showed no significant difference between the two series (p < 0.12638). The development of conduction velocity depression was clearly dose-dependent. Drug suppression test with procamide + propanolol resulted in noninducibility of sVT in 115 patients, with strong significant difference from when the drug was used alone (p < 0.0015). Better results at EPS were obtained by the combination amiodarone + propaphenone, although no additional benefit was reported when compared with amiodarone alone. CONCLUSIONS: In conclusion, antiarrhythmic drugs with class I action may be highly effective in terminating sVI (lidocaine, procamide) but may be ineffective in preventing it or even arrhythmogenic. According to our data, drugs with class III antiarrhythmic action showed significantly different behavior: they were more effective in prolonging refractoriness and reducing the excitable gap at longer cycle lengths and, thus, capable of preventing, rather than terminating. Although statistical difference was reported between the amiodarone-treated group and the control group, the incidence of recurrent sVT remained too high to consider drug therapy as

Left ventricular dynamics after aortic valve replacement: a long-term, combined radionuclide angiographic and ultrasonographic study.

Between January 1985 and July 1990, we studied 71 patients at our institution who underwent aortic valve replacement for either aortic valve regurgitation (40 patients) or stenosis (31 patients). The following prostheses were implanted: 25 St. Jude Medical valves (bileaflet), 16 Björk-Shiley (monoleaflet, tilting disc, 60 degrees convexo-concave), 16 Medtronic-Hall (monoleaflet, tilting disc), and 14 Starr-Edwards (caged ball). The patients were evaluated pre-and postoperatively by means of gated blood-pool scintigraphy and Doppler echocardiography. Postoperatively, each patient was studied at 6 months, 1 year, and then annually. The evaluations focused upon 1) scintigraphically assessed left ventricular performance indicators (end-diastolic and end-systolic volume, as well as resting and exercise ejection fraction) and 2) Doppler-derived hemodynamic indexes (peak and mean transvalvular pressure gradient, effective orifice area, regurgitant flow, and systolic wall stress). Early after aortic valve replacement, 55 (77.5%) of the patients had substantial symptomatic relief, with normal hemodynamic values both at rest and during exercise (New York Heart Association functional class I or II); another 6 patients (8.5%) maintained their preoperative status in those classes. Within a year after surgery, a majority of patients showed a significant reduction in left ventricular dimensions. The patients with preoperative aortic valve stenosis had a significantly reduced end-diastolic and end-systolic volume (p<0.05), a moderately reduced left ventricular mass index (p<0.01), and a significantly increased exercise ejection fraction (p<0.05); moreover, in all 31 of these cases, systolic wall stress returned to normal or lower-than-control values (p<0.005). The patients with preoperative aortic valve regurgitation had a significant reduction in end-diastolic and end-systolic volume (p<0.005), diastolic wall stress (p<0.005), and a significant increase in exercise ejection fraction (p<0.01); however, their left ventricular mass index was not significantly reduced. Optimal long-term survival was afforded by the St. Jude valve in the small size (21 mm) and the Starr-Edwards valve in the large size (27 mm). This study represents the first reported use of a serial, combined radionuclide and echocardiographic procedure for the follow-up of patients undergoing aortic valve replacement. During the 5(1/2)-year follow-up period, this combined technique proved highly accurate for collecting follow-up data, often complementing or correcting simple ultrasound results. This diagnostic approach enabled us to 1) obtain information comparable to or better than that provided by cardiac catheterization, 2) identify complications early, 3) differentiate between valvular and ventricular failure, and 4) suggest the valve of choice (not always that with the best hemodynamic performance) in patients with different cardiac variables. Further research is needed to confirm this study, the results of which could change many medical and surgical strategies for clinical management of the diseased aortic valve.

Doppler hemodynamic characteristics of four widely used aortic valve prostheses.

Fifty-one patients with normofunctioning aortic prosthetic heart valves were evaluated by Doppler-Echocardiography to determine type-related flow characteristics. The four mechanical valves tested were: Starr-Edwards (1200-1260 aortic), Bjork-Shiley (60 degrees-60 degrees cc aortic), Medtronic-Hall (aortic) and St. Jude Medical (aortic). The most significant dynamic indexes were calculated: Peak (PG) and Mean (MG) Gradient across the valve, Cardiac Index (CI) or Cardiac Output (CO), Regurgitant Jets, Effective Orifice Area (EOA), Spectral Diagram Systolic Trend (SDST) and PVRT (time required to reach peak velocity during systole)/LVET (left ventricular ejection time) Ratio. Patients with Doppler assessed prosthetic dysfunction were dropped out of the study group. As expected, significant reverse correlation (-0.70) was found when transvalvular pressure gradients were compared with valve size. Significant direct correlation (0.82) was found when EOA was compared with valve size, thus suggesting the high reliability of the continuity equation in the assessment of the real orifice area. The Starr-Edwards valve, when compared with the other prostheses of the same size, showed the highest calculated transvalvular gradient; the St. Jude Medical showed the lowest. On the other hand, the Starr-Edwards valve was not commonly associated with regurgitation, while the St. Jude valve was usually moderately incompetent. Those hemodynamic differences should guide the selection of the ideal prosthetic valve for elective surgical indications. Doppler measurements provided noninvasive information similar to that given by cardiac catheterisation, which was reproducible and specific for valve function. According to this high sensitivity and specificity and to the absolute innocuity of the procedure, Doppler-Echocardiography should be considered the elective technique for long-term follow-up in patients with aortic prosthetic heart valves.