Description of regional mitral annular nonplanarity in healthy human subjects: A novel methodology

ObjectiveFinite-element analysis demonstrates that the nonplanar shape of the mitral annulus diminishes mitral leaflet stress. It has therefore been postulated that repair with annuloplasty rings that maintain the nonplanar shape of the annulus could increase repair durability. Although the global nonplanarity of the mitral annulus has been adequately characterized, design of such a ring requires a quantitative description of regional annular geometry. By using real-time 3-dimensional echocardiography in conjunction with available image processing software, we developed a methodology for describing regional annular geometry and applied it to the characterization of the normal human mitral annulus.MethodsFive healthy volunteers underwent mitral valve imaging with real-time 3-dimensional echocardiography. Regional annular height was calculated at 36 evenly spaced intervals.ResultsMaximal annular height/commissural width ratio was found to occur at the midpoint of the anterior annulus in all cases. These values averaged 26% ± 3.1%, whereas those for the midposterior annulus averaged 18% ± 3.0%. The average commissural width was 35.2 ± 6.0 mm. Although substantial spatial heterogeneity was observed, regional annular height at a given rotational position was highly conserved among subjects when normalized to commissural width.ConclusionsThese quantitative imaging and analytic techniques demonstrate that the normal human mitral annulus is regionally heterogeneous in its nonplanarity, and they establish a means of describing annular geometry at a regional level. With wider application, these techniques may be used both to characterize pathologic annular geometry and to optimize the design of mitral valve annuloplasty devices

Surgical treatment of ischemic mitral regurgitation might not influence ventricular remodeling

ObjectivesSurgical treatment for ischemic mitral regurgitation has become more aggressive. However, no clinical study has demonstrated that surgical correction of chronic ischemic mitral regurgitation improves survival. We used 4 well-developed ovine models of postinfarction left ventricular remodeling to test the hypothesis that ischemic mitral regurgitation does not significantly contribute to postinfarction left ventricular remodeling.MethodsInfarction of 21% to 24% of the left ventricular mass was induced by means of coronary ligation in 77 sheep. Infarctions varied only by anatomic location in the left ventricle: anteroapical, n = 26; anterobasal, n = 16; laterobasal, n = 9; and posterobasal, n = 20. Six additional sheep had ring annuloplasty before posterobasal infarction. End-systolic and end-diastolic left ventricular volume, end-systolic muscle-to-cavity area ratio, left ventricular sphericity, ejection fraction, and degree of ischemic mitral regurgitation, as determined by means of quantitative echocardiography, were assessed before infarction and at 2, 5, and 8 weeks after infarction.ResultsAll infarcts resulted in significant postinfarction remodeling and decreased ejection fraction. Anteroapical infarcts lead to left ventricular aneurysms. Only posterobasal infarcts caused severe and progressive ischemic mitral regurgitation. Remodeling because of posterobasal infarcts was not more severe than that caused by infarcts at other locations. Furthermore, prophylactic annuloplasty prevented the development of mitral regurgitation after posterobasal infarction but had no effect on remodeling.ConclusionThe extent of postinfarction remodeling is determined on the basis of infarct size and location. The development of ischemic mitral regurgitation might not contribute significantly to adverse remodeling. Ischemic mitral regurgitation is likely a manifestation rather than an important impetus for postinfarction remodeling

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

The dynamic anterior mitral annulus.

BACKGROUND: The anterior mitral annulus is considered a fixed structure. Recent data suggest otherwise. This study tested the hypothesis that the size of the anterior annulus varies with hemodynamic loading and ventricular contractility. METHODS: Sonomicrometry array localization measured annular area, total annular circumference, anterior circumference, and posterior circumference in 6 sheep before and after neosynephrine increased systolic blood pressure by at least 150% during atrial pacing at 120 beats/min. In 6 additional animals the same dimensions were measured during atrial pacing (at 120 and 150 beats/min) and during isoproteronol infusions to increase heart rate to 120 and 150 beats/min. RESULTS: Neosynephrine increased systolic total annular circumference from 99.7 +/- 5.5 mm to 106.9 +/- 9.6 mm. Anterior circumference increased from 40.8 +/- 4.0 mm to 45.3 +/- 5.7 mm whereas posterior circumference only increased from 59.0 +/- 5.5 mm to 61.6 +/- 7.0 mm. Low isoproteronol infusion decreased systolic total annular circumference from 107.5 +/- 8.3 mm to 101.9 +/- 10.6 mm. Most of this change occurred in the posterior circumference. Higher infusions of isoproteronol decreased total annular circumference from 106.8 +/- 8.3 mm to 98.3 +/- 9.7 mm. At this higher inotropic state the decrease in annular size was similar in the anterior and posterior annulus. CONCLUSIONS: In sheep, the anterior annulus is a dynamic structure that varies in size in response to changes in hemodynamic loading and ventricular contractility

Quantification and localization of mitral valve tenting in ischemic mitral regurgitation using real-time three-dimensional echocardiography.

OBJECTIVE: Ischemic mitral regurgitation (IMR) results from a variable combination of annular dilatation and remodeling of the subvalvular apparatus. Current surgical techniques effectively treat annular dilatation, but methods for addressing subvalvular remodeling have not been standardized. An effective technique for determining the extent of subvalvular remodeling could improve surgical results by identifying patients who are unlikely to benefit from annuloplasty alone. METHODS: A well-characterized ovine model of IMR was employed. Real-time three-dimensional echocardiography was performed on each animal at baseline, immediately after infarction and 8 weeks after infarction. Intercommissural width and mitral annular area were calculated for each subject at each time point. Mitral valve tenting area and height were calculated at discrete intervals along the entire intercommissural axis. The location at which maximal tenting area and height occurred was recorded. Mitral valve tenting volume was calculated by summation. RESULTS: Both immediate and long-term increases were observed in mean intercommissural width and mean mitral annular area (from 33.2 to 36.3 to 39.7 mm and from 740 to 810 to 1020 mm(2), respectively). Both immediate and long-term increases were observed in maximum mitral valve tenting area and height (from 38.5 to 50.6 to 112.1mm(2) and from 3.9 to 4.7 to 10.1mm, respectively). Mitral valve tenting area and height at the mid-point of the intercommissural axis did not change significantly during the observation period. The position along the intercommissural axis at which maximal mitral valve tenting area and height occurred shifted progressively toward the anterior commissure (from 51.8% to 45.1% to 38.9% and from 52.9% to 45.1% to 37.8%). Both immediate and long-term increases were observed in mitral valve tenting volume (from 474.0 to 622.1 to 1483.5mm(3)). CONCLUSIONS: We have described a technique that utilizes real-time three-dimensional echocardiography to perform a comprehensive assessment of leaflet tethering on the entire mitral valve. Our methodology is not influenced by viewing plane selection, regional tenting asymmetry, or annular dilatation and, therefore, represents a potentially useful surrogate measure of subvalvular remodeling

Regional and global patterns of annular remodeling in ischemic mitral regurgitation.

BACKGROUND: The mammalian mitral annulus is saddle shaped. Experimental studies have shown that loss of saddle shape occurs in ischemic mitral regurgitation. However, neither the temporal pattern of global annular remodeling nor the geometric pattern of regional annular remodeling has been described. We sought to characterize these changes using real-time three-dimensional echocardiography in an ovine model. METHODS: Ten sheep underwent real-time three-dimensional echocardiography at baseline and 1 hour and 8 weeks after posterobasal myocardial infarction. Multiple mitral annular geometric indexes were measured at each time point to assess regional and global annular remodeling. RESULTS: One hour after infarction, global annular height decreased from 5.8 +/- 0.5 mm to 4.0 +/- 0.4 mm (p \u3c 0.001) while intercommissural width increased from 29.0 +/- 1.3 mm to 35.7 +/- 1.7 mm (p = 0.023), resulting in a decrease in the global annular height to commissural width ratio from 20.0% +/- 1.6% to 11.2% +/- 0.9% (p \u3c 0.001). Eight weeks after infarction, global annular height decreased to 3.9 +/- 0.2 mm (p \u3c 0.05) while intercommissural width increased to 40.7 +/- 1.5 mm (p \u3c 0.001), resulting in an additional decrease in the global annular height to commissural width ratio to 9.4% +/- 0.4% (p \u3c 0.001). Although annular remodeling involved the entire mitral annulus, there was regional heterogeneity in its extent. CONCLUSIONS: Significant global annular flattening and dilatation occur during the development of ischemic mitral regurgitation in an ovine model. Regional annular remodeling is heterogeneous and is not limited the posterior commissure or the posterior annulus

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\u27s 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 diameter

Role of acetaminophen in acute myocardial infarction.

Acetaminophen, the active ingredient in Tylenol, is a widely used drug that is well known for its analgesic and antipyretic properties. Acetaminophen is a commonly used alternative to nonsteroidal anti-inflammatory drugs, which have recently been demonstrated to increase mortality after acute myocardial infarction (AMI). The safety and potential cardioprotective properties of acetaminophen in the setting of AMI have recently been investigated; however, the results from these studies have been inconclusive. Using both large (ovine) and small (rabbit) collateral-deficient animal models, we studied the effects of acetaminophen in the setting of reperfused AMI. In both species we studied the effects of acetaminophen on myocardial salvage and ventricular function. Additionally, we studied the effects of acetaminophen on myocardial perfusion in sheep and on myocyte apoptosis in rabbits. Sixteen sheep and twenty-two rabbits were divided into two groups and administered acetaminophen or a vehicle before undergoing ischemia and reperfusion. The ischemic period was 60 min in sheep and 30 min in rabbits. All animals were reperfused for 3 h. There were no significant differences observed in myocardial perfusion, myocyte apoptosis, or infarct size in acetaminophen-treated animals. Acetaminophen increased cardiac output and mean arterial pressure before ischemia in sheep but had no effect on any other hemodynamic parameter. In rabbits, no effect on cardiac output or blood pressure was detected. These results support the role of acetaminophen as a safe drug in the postmyocardial infarction setting; however, no significant cardioprotective effect of the drug could be demonstrated