Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation and hypoperistalsis of the gut and pulmonary hypertension.

BACKGROUND Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change (±SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (−0.139±0.013 and −0.107±0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.)

Surgical progress has not influenced late risks for death, re-operation or PVR in adults with repaired tetralogy of Fallot. Instead, reduction of early surgical mortality to <2% is responsible for excellent late survival >90% overall. The constant risk of PVR is low and independent of repair type. Baseline morphologic features are important determinants of late outcome.

Background-Cardiovascular pathology, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in a FBN1-targeted mouse model of MFS with aortic pathology similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture.

With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. Part II of the guidelines includes recommendations for the care of patients with left ventricular outflow tract obstruction and bicuspid aortic valve disease, coarctation of the aorta, right ventricular outflow tract obstruction, tetralogy of Fallot, Ebstein anomaly and Marfan's syndrome. Topics addressed include genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy risk and follow-up requirements. The complete document consists of four manuscripts that are published online in the present issue of The Canadian Journal of Cardiology. The complete document and references can also be found at www.ccs.ca or www.cachnet.org.

OBJECTIVE-Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).RESEARCH DESIGN AND METHODS-Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR Ն135 ml/min per 1.73 m 2 ), and 12 subjects exhibited normofiltration (GFR Ͻ135 ml/min per 1.73 m 2 ).RESULTS-Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 Ϯ 5 to 139 Ϯ 5 ml/min per 1.73 m 2 ) but increased GFR in the normofiltration group (118 Ϯ 5 to 138 Ϯ 5 ml/min per 1.73 m 2 ). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.CONCLUSIONS-In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states. Diabetes 57: 688-695, 2008 A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3-5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.Animal studies have examined the role of vasodilatation (7) in the pathogenesis of hyperfiltration. Early work focused on the role of cyclooxygenase (COX)-derived prostanoids, which exert a variety of functions in the kidney, including important vasodilatory effects; however, studies initially used nonspecific COX1/COX2 inhibitors (8). With the discovery of the COX2 isoform and selective COX2 inhibitors, experimental models of diabetes revealed that COX2 expression is increased in the macula densa in this condition and is associated with enhanced production of vasodilatory prostaglandins, RAS activation, and renal hyperfiltration (9). Moreover, in streptozotocininduced diabetic rat models with a renal hyperfiltration phenotype, hyperglycemia-associated prostaglandin production and hyperfiltration were blunted using COX2 inhibition (9). Given the association between renal hyperfiltration, intraglomerular hypertension, and nephropathy related to diabetes (7,10,11), the elucidation of COX2-mediated renal hemodynamic function changes in dia...

Objective-To perform a systematic review and meta-analysis to examine whether rheumatic disease is associated with an increased carotid intima-media thickness (CIMT; increasingly used as a surrogate marker for atherosclerosis) when compared with healthy control subjects. Methods and Results-A prespecified search strategy was used to identify relevant studies in the MEDLINE and EMBASE databases (January 1, 1986 to December 31, 2008. Methodological quality was assessed using the Newcastle-Ottawa score for observational studies. A total of 68 controlled comparisons from 60 different studies were reviewed: 25 (37%) on rheumatoid arthritis, 24 (35%) on systemic lupus erythematosus, 6 (9%) on systemic sclerosis, and 13 (19%) on other rheumatic diseases. Random-effects meta-regression analysis was performed. The estimated summary effect size between control and study subject CIMT measurement comparisons, with preexisting cardiovascular disease excluded, was 0.64 (95% CI, 0.46 to 0.82). This represented an overall absolute mean difference of 0.06 mm (95% CI, 0.05 to 0.06 mm). Preexisting cardiovascular disease, rheumatic disease type, and disease duration contributed to heterogeneity. Conclusion-Accelerated atherosclerosis is a common complication of autoimmune rheumatic diseases, with early changes seen even in pediatric patients. CIMT was significantly increased in rheumatic disease populations. Future studies need to use a standardized protocol to ensure clinically meaningful results when measuring CIMT as a surrogate for premature atherosclerosis.

Objectives We explored the association of noncoronary cardiac abnormalities with coronary artery dilation and with laboratory inflammatory markers early after Kawasaki disease (KD) diagnosis. Background Left ventricular (LV) dysfunction, mitral regurgitation (MR), and aortic root dilation occur early after diagnosis; their associations with coronary artery dilation and inflammatory markers have not been well-described. Methods Centrally interpreted echocardiograms were obtained at KD diagnosis and 1 and 5 weeks after diagnosis on 198 subjects in the National Institutes of Health-sponsored Pediatric Heart Network KD pulsed steroid trial. Regression models were constructed to investigate the relationships among early LV dysfunction, MR, and aortic root dilation with coronary artery dilation and laboratory inflammatory markers. Results At diagnosis, LV systolic dysfunction was present in 20% of subjects and was associated with coronary artery dilation, seen in 29% (p = 0.004). Although LV dysfunction improved rapidly, LV dysfunction at diagnosis predicted greater odds of coronary artery dilation at 1 and 5 weeks after diagnosis (5-week odds ratio: 2.7, 95% confidence interval: 1.2 to 6.3). At diagnosis, MR was present in 27% of subjects and aortic root dilation was present in 8%; each was associated with larger coronary artery size at diagnosis. Left ventricular dysfunction was associated with higher erythrocyte sedimentation rate and, at diagnosis only, lower serum albumin; MR was associated with higher erythrocyte sedimentation rate and lower albumin at all times. Aortic root size had little association with inflammatory markers. Conclusions Noncoronary cardiac abnormalities are associated with coronary artery dilation and laboratory evidence of inflammation in the first 5 weeks after KD, suggesting a shared inflammatory mechanism. (Trial of Pulse Steroid Therapy in Kawasaki Disease [A Trial Conducted by the Pediatric Heart Network]; NCT00132080)