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Background: Cardiovascular disease, 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 an FBN1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture., Methods: The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions., Conclusion: This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.

Diabetes incidence is increasing rapidly in the United States. Diabetes increases the risk for cardiovascular disease, the major cause of death in diabetic individuals. The conventional cardiovascular risk factors of hyperlipidemia and hypertension worsen diabetic vascular disease. Treatment targets for low-density lipoprotein cholesterol (LDL-C) and blood pressure in diabetic individuals are being debated. The SANDS is a randomized, open-label, 3-year trial to examine the effects of aggressive LDL-C (goal <70 mg/dL) and blood pressure (BP) (goal <115/75 mm Hg) reduction versus the standard goals of <100 mg/dL for LDL-C and <130/85 mm Hg for BP. Five hundred forty-nine American-Indian men and women >40 years old with type 2 diabetes were randomized to 1 of 2 groups. Lipids and BP are managed using Food and Drug Administration-approved medications in an algorithmic approach. The presence and progression of atherosclerosis are evaluated by carotid ultrasonography; echocardiography assesses cardiac function. The primary end point is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events. These outcomes are combined by using a ranked analysis for carotid thickness and assigning a "worst rank" for a cardiovascular event. Secondary end points include carotid plaque score, left ventricular geometry and function, serum C-reactive protein, and safety measures. Unique aspects of the study design and analysis plan involve the use of a composite outcome and changes during the trial of LDL-C treatment goals for participants with baseline or incident cardiovascular disease in the conventional group because of changes in the standard of care. Study results will further understanding of the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in US populations and will help determine optimal LDL-C and BP treatment goals for diabetic patients.

Background: Echocardiographic left atrial (LA) volume has been documented to be an independent predictor of cardiovascular events. Less is known about the predictive ability of anteroposterior LA diameter, a simpler measure of LA size obtained routinely during echocardiographic evaluation., Methods: We investigated the prognostic value of LA diameter for incident cardiovascular events in 2804 American Indians free of clinical cardiovascular disease, valvular disease, and atrial fibrillation. Echocardiographic variables were obtained using standardized methods, and previously derived sex-specific partition values were used to define left ventricular (LV) hypertrophy indexed to height(2.7) (in meters) and LA enlargement (> 4.2 cm in men, > 3.8 cm in women). Cardiovascular events included nonfatal stroke, coronary heart disease, congestive heart failure, and fatal cardiovascular disease based on validated definitions., Results: During a median follow-up of 7 years, 368 events occurred. LA diameter, both as a continuous and as a categorical variable, was significantly associated with incident cardiovascular events in unadjusted analyses. In multivariable analyses that adjusted for age, sex, body mass index, hypertension, diabetes, total cholesterol-high-density lipoprotein cholesterol, smoking, renal insufficiency, LV hypertrophy, abnormal LV systolic and diastolic function, mitral annular calcification, fibrinogen, and C-reactive protein, both LA diameter (risk ratio 1.04/mm, 95% CI 1.02-1.07, P < .002) and LA enlargement (risk ratio 1.57, 95% CI 1.17-2.10, P = .002) remained independent predictors of first cardiovascular events., Conclusions: In this population-based cohort, LA diameter independently predicted incident cardiovascular events after adjustment for established clinical, echocardiographic, and inflammatory risk factors. This simple measure of LA dilatation can identify individuals at heightened risk who may warrant more aggressive risk factor modification.

Background: Although echocardiography is commonly used to assess left ventricular (LV) systolic function, few data are available concerning the prognostic significance of LV ejection fraction (EF) calculated from linear echocardiographic measurements or 2-dimensional (2-D) wall motion scores in population-based samples., Methods: Echocardiography was used in the second Strong Heart Study (SHS) examination to calculate LV EF in 2948 American Indians without prevalent coronary heart disease; 2923 had 2-D wall motion scores., Results: Mildly and severely reduced LV EF occurred in 10% and 2% of participants, was associated with older age, male sex, higher systolic pressure, heart rate and markers of renal disease and inflammation. During 37 +/- 9 months follow-up, cardiovascular death occurred in 2%, 5% and 12% of participants with normal, mildly reduced and severely reduced EF; all cause mortality rates were 6%, 10% and 32% (both P <.001). In Cox proportional hazards analyses, adjusting for covariates, cardiovascular death was higher with mildly reduced EF (risk ratio [RR] 2.9, 95% CI 1.6-5.4, P =.0007) and especially with severely reduced EF (RR 6.9, 95% CI 3.0-15.9, P <.0001); all-cause mortality was increased with severe LV dysfunction (RR 4.8, 95% CI 2.8-8.1, P <.001) and marginally with mildly reduced EF (odds ratio 1.4, 95% CI 0.95-2.15, P =.08). Segmental LV dysfunction and mildly and severely reduced EF from 2-D wall motion scores were associated with 3.3-fold (95% CI 1.1-9.4, P =.02), 3.5-fold (95% CI 2.1-5.8) and 3.8-fold (95% CI 1.9-7.6) (all P <.001) increased rates of cardiovascular death., Conclusions: LV EF from linear echocardiographic measurements as well as segmental LV dysfunction and EF from 2-D wall motion scores strongly and independently predict cardiovascular mortality. Reduced EF by simple echocardiographic method has estimated population-attributable risks of about 35% for cardiovascular death and 12% for all-cause mortality in a population-based sample of middle-aged to elderly adults.

Background: It has been reported that aortic regurgitation, mitral valve regurgitation, or both are associated with lower body mass index, an index of body adiposity. However, the relations of valvular regurgitation to body composition and myocardial bioenergetic expenditure have not been previously investigated in a population-based sample., Methods: We selected 1496 patients with hypertension who did not have diabetes mellitus to participate in the Hypertension Genetic Epidemiology Network (HyperGEN) study. We excluded participants with severe aortic or mitral stenosis or with known coronary heart disease. Bioimpedance was used to assess body composition. Echocardiography was used to assess left ventricular (LV) structure and function and to calculate myocardial workload (expressed as energy expenditure) from end-systolic stress, ejection time, and stroke volume. The study sample was divided into groups without mitral or aortic regurgitation (control subjects, n = 1175), with mild valvular regurgitation (1+, n = 246), and with at least moderate (>or=2+) mitral or aortic regurgitation (n = 75)., Results: The mean patient age was higher with more severe valvular insufficiency. Sex distribution and blood pressure were similar among the 3 groups. Body mass index and fat mass were significantly lower with more severe valvular regurgitation, whereas fat-free mass was only slightly lower in the group with >or=2+ regurgitation compared with control subjects. Skinfold thicknesses (brachial and subscapular) were lower with more severe valvular regurgitation, whereas self-reported physical activity per week was similar among the 3 groups. LV mass and circumferential end-systolic stress were higher with more severe valvular regurgitation. Noninvasively estimated myocardial energy expenditure was slightly higher in participants with 1+ valvular regurgitation and was significantly higher with >or=2+ regurgitation. Ejection fraction was mildly lower with >or=2+ aortic insufficiency, mitral insufficiency, or both. Midwall shortening and stress-corrected midwall shortening did not differ among groups., Conclusions: In a population-based sample of adults with hypertension and without diabetes mellitus, known coronary heart disease, or significant valvular stenosis, mitral and aortic regurgitation were associated with higher LV mass and total myocardial biomechanical workload but with lower body fat mass and slightly lower body fat-free mass, which suggests that global myocardial bioenergetic expenditure is elevated by concomitant valvular regurgitation beyond the effect of pressure overload caused by hypertension.

Background: It is unclear whether fibrinogen predicts cardiovascular events independently of echocardiographic cardiovascular abnormalities and traditional risk factors., Methods: We studied 2671 American Indians who participated in the second Strong Heart Study examination (1993-1995) and were observed for an average of 50 +/- 6 months. Participants with baseline overt coronary artery disease or a plasma creatinine level > or =3 mg/dL were excluded. Left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial contractility were assessed by echocardiography., Results: Prevalences of echocardiographic abnormalities and cardiovascular event rates were higher with higher fibrinogen levels. Incident cardiovascular events (n = 158) and deaths (n = 64) were more frequent in participants with elevated fibrinogen levels (>400 mg/dL) than in participants with lower fibrinogen levels, as was the prevalence of echocardiographic abnormalities (both P <.01). Incident cardiovascular fatal and nonfatal events and cardiovascular deaths were 4 and 8 times higher, respectively, in participants with both elevated fibrinogen levels and echocardiographic abnormalities than in participants with neither echocardiographic abnormalities nor elevated fibrinogen levels. However, participants with fibrinogen levels >400 mg/dL had a 2 times greater relative risk of cardiovascular events or mortality, independent of both risk factors and echocardiographic abnormalities., Conclusions: In a population-based sample of adults without clinical evidence of coronary artery disease at baseline, fibrinogen levels predicted cardiovascular events independent of traditional risk factors, left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial systolic function.

Background: It has been hypothesized that the level of end-systolic wall stress (sigma(m)) is a feedback signal that regulates the level of hypertrophy. Thus, low levels of sigma(m) may signify inappropriate hypertrophy., Methods: To characterize left ventricular (LV) structure and systolic function in hypertensive subjects with low levels of sigma(m), we studied 763 patients. LV function was studied by midwall stress-shortening analysis. Partition values for sigma(m) were derived from a separate group of normal subjects, and the study population was divided into low stress (group I, n = 136), high stress (group III, n = 157), and intermediate stress group II (n = 470). LV chamber and myocardial function were characterized by relating shortening at the endocardium and at the midwall, respectively, to stress., Results: As expected, group III patients had the highest values for systolic blood pressure and LV cavity size but the lowest values for wall thickness and relative wall thickness. Surprisingly, however, there were no significant differences among stress groups with regard to age or body mass index. Contrary to the hypothesis that low levels of stress are indicative of excessive hypertrophy, there were no significant differences among the 3 groups with regard to LV mass or any form of LV mass index. Furthermore, despite lower mean values for afterload, group I patients had significantly lower values for midwall shortening, and this finding was indicative of reduced myocardial function; stress-shortening plots demonstrated that 28% of group I patients fell below 95% CI compared with 10% of group II and only 5% of group III patients., Conclusions: Hypertensive subjects with low values for sigma(m) have more concentric LV geometry (higher relative wall thickness) and, on average, reduced myocardial function.

Background: We have identified increased left ventricular (LV) mass, wall thickness, relative wall thickness, and reduced systolic function in diabetic individuals after adjusting for blood pressure and body mass index. However, the cardiovascular correlates of impaired glucose tolerance (IGT), a precursor of diabetes, are unknown., Methods: We compared LV measurements between 457 American Indian participants in the Strong Heart Study with IGT (34% men) by World Health Organization criteria and 888 participants (49% men) with normal glucose tolerance., Results: Participants with IGT were older (60 vs 59 years, P < .01), more overweight (body mass index, 32 +/- 6 vs 29 +/- 5 g/m(2)), and had higher systolic blood pressure (129 +/- 20 vs 124 +/- 18 mm Hg, P < .001) and heart rate (67 +/- 10 vs 66 +/- 11 beats/min, P = .011). In univariate analyses, women but not men with IGT had higher LV mass (mean, 150 vs 138 g, P < .001) and cardiac index (2.6 vs 2.5 L/min/m(2), P < .05). LV wall thicknesses and relative wall thickness were greater in women and men with IGT. Regression analysis, adjusting for multiple covariates in the entire study population, identified independent associations of IGT with higher LV relative wall thicknesses, LV mass/height(2.7), and cardiac output/height(1.83)., Conclusions: IGT is associated with increased LV wall thickness, mass, and cardiac output independent of effects of relevant covariates.

Background: Although clinical congestive heart failure (CHF) is increasingly common, few data document the prevalence and correlates of underlying left ventricular (LV) systolic dysfunction (D) in population-based samples., Methods: Echocardiography was used in the second Strong Heart Study (SHS) examination to identify mild and severe LVD (LV ejection fraction [EF] 40%-54% and <40%, respectively) in 3184 American Indians., Results: Mild and severe LVD were more common in men than women (17.4% vs 7.2% and 4.7% vs 1.8%) and in diabetic than nondiabetic participants (12.7% vs 9.1% and 3.5% vs 1.6%). Stepwise increases were observed from participants with normal EF to those with mild and severe LVD in age (mean 60 vs 61 and 63 years, P <.001), prevalence of overt CHF (2% vs 6% and 28%) and definite coronary heart disease (3% vs 11% and 32%), systolic pressure (129 vs 135 and 136 mm Hg), serum creatinine level (0.98 vs 1.34 and 2.16 mg/dL), and log urinary albumin/creatinine level (3.2 vs 3.7 and 4.7); a negative relation was seen with body mass index (31.1 vs 31.0 and 28.4 kg/m(2)) (all P <.001). In multivariate analyses lower LVEFs were independently associated with clinical CHF and coronary heart disease, lower myocardial contractility, male sex, hypertension, overweight, arterial stiffening (higher pulse pressure/stroke volume) and renal dysfunction (higher serum creatinine level), higher LV mass, and lower relative wall thickness., Conclusions: LVD, present in approximately 14% of middle-aged to elderly adults, is independently associated with overt heart failure and coronary heart disease, male sex, hypertension, overweight, arterial stiffening, and renal target organ damage and, less consistently, with older age and diabetes.

The relationship of combined rest and exercise electrocardiographic (ECG) repolarization abnormalities to left ventricular geometry and function was examined in 48 patients with asymptomatic chronic pure aortic regurgitation and no recent use of digitalis. Echocardiographic and radionuclide cineangiographic findings were compared in groups defined by the presence or absence of the "strain" pattern of repolarization abnormality on the resting ECG and also by the presence or absence of standard positive repolarization changes during upright treadmill exercise ( > 0.1 mV additional horizontal or downsloping ST depression). These hierarchic groups demonstrated trends toward progressively abnormal left ventricular dimensions, mass, wall stress, and change in ejection fraction with exercise. Although the presence of the strain pattern on the resting ECG alone was most strongly correlated with underlying functional and geometric abnormalities, an abnormal exercise test response was independently associated with abnormal left ventricular systolic dimension. The large group of patients with no symptoms and normal resting repolarization had only 0% to 4% prevalences of markedly increased systolic dimension (> 55 mm), reduced ejection fraction at rest (< 45%), or reduced ejection fraction during exercise (< 40%), whereas the small group of patients with abnormal resting repolarization and a positive exercise test response had 50% to 83% prevalences of these findings. These data suggest a possible role for rest and exercise ECG in the serial evaluation of patients with aortic regurgitation.

To determine whether rheumatic fever is associated with mitral valve prolapse (MVP) diagnosed by echocardiography, records from 561 subjects participating in a prospective family study were reviewed. The prevalence of a history of rheumatic fever by modified Jones criteria was determined in 92 probands and 112 affected relatives or spouses with M-mode and two-dimensional echocardiographic findings of MVP, accompanied in most instances by classic auscultatory findings, and in 357 family members without MVP. The prevalence of rheumatic fever was 5.4% in both MVP sub-groups and 2.2% in the family members without MVP (p<0.05 vs the combined MVP group). However, people with a history of rheumatic fever were older than the remaining subjects (48 +/- 17 vs 36 +/- 20 years, p<0.01) as expected because of the decline in rheumatic fever in the twentieth century, and subjects with MVP were older than subjects without MVP (39 +/- 16 vs 34 +/- 22 years, p<0.01). Multiple logistic regression showed that after the independent relation of older age with a positive history of rheumatic fever (p<0.01) was taken into account, there was a trend toward a lower likelihood of previous rheumatic fever associated with MVP (odds ration 0.42, p=0.07). These results do not support either a true association or a causal role of rheumatic fever in the pattern of mitral leaflet motion and auscultatory abnormalities in adults, for which the term MVP is generally used.

Although atrial natriuretic factor is primarily of atrial origin, recent observations indicate that the hormone is also synthesized by hypertrophied left ventricular myocardium. To assess the separate influences of left ventricular and left atrial dilatation and left ventricular hypertrophy on human atrial natriuretic factor levels, left atrial dimension and volume and left ventricular dimension and mass were compared in 49 normal subjects, in 33 patients with chronic aortic regurgitation, and in 15 patients with chronic mitral regurgitation. When compared with normal subjects, patients with chronic aortic and mitral regurgitation had similarly dilated and hypertrophied left ventricles (p less than 0.0005), while only mitral regurgitation patients had significantly enlarged (p less than 0.0005) mean left atrial dimension and volume. Likewise, plasma atrial natriuretic factor was elevated among patients with mitral regurgitation (60.3 +/- 47.0 fmol/ml) but was normal in patients with aortic regurgitation (19.0 +/- 11.0 fmol/ml versus 12.4 +/- 5.2 fmol/ml in normals; both p less than 0.0005 versus mitral regurgitation). Among all 97 subjects, atrial natriuretic factor levels correlated more closely with left atrial dimension and volume (r = 0.62 and 0.64, p less than 0.0005) than with left ventricular dimension (r = 0.44, p less than 0.0005) or mass (r = 0.40, p less than 0.0005). In addition, multivariate analysis indicated that left atrial volume bore a stronger independent relationship to plasma atrial natriuretic factor levels than either age or left ventricular variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Although aortic valve replacement for aortic regurgitation relieves left ventricular volume overload, ventricular geometry does not consistently normalize. To assess the extent, determinants, and functional consequences of reversal of left ventricular dilatation and hypertrophy, 38 patients with severe aortic regurgitation were studied pre- and postoperatively by serial echocardiography and radionuclide cineangiography. Left ventricular end-diastolic dimension normalized in 58% of patients by 9 +/- 6 months postoperatively, at which time 50% of patients had normalized mass; cumulative normalization rose to 66% for end-diastolic dimension and 68% for left ventricular mass during further follow-up. All patients who had normalized end-diastolic dimension also had normal postoperative ejection fractions (mean 61 +/- 8%). In contrast, patients in whom the left ventricle remained dilated had a 42% prevalence of subnormal postoperative left ventricular ejection fraction. Preoperative left ventricular end-systolic dimension less than or equal to 55 mm identified 86% of patients in whom end-diastolic dimension normalized, whereas end-systolic dimension exceeded 55 mm in 81% of those with persistent dilatation; other proposed preoperative predictors of operative outcome correctly identified lower proportions (from 59% to 71%) of patients in whom left ventricular size did or did not normalize. In conclusion, aortic valve replacement resulted in normalized left ventricular chamber size and mass in two thirds of the patients selected for operation by current criteria; favorable geometric outcome is associated with persistence or recovery of normal left ventricular function.

The exercise ECGs of 30 patients with pure aortic regurgitation (AR) were compared with functional and geometric variables measured by echocardiography and radionuclide cineangiography. The 10 patients with positive ECG responses to exercise (greater than or equal to 0.1 mV additional downsloping or horizontal ST segment depression) were similar to the 20 patients with negative tests with respect to mean age, exercise duration, peak work load achieved, symptoms, and resting ECG findings. Patients with positive exercise tests had significantly reduced left ventricular (LV) ejection fractions at rest (44 +/- 4% vs 52 +/- 2%) and during peak exercise (38 +/- 3% vs 48 +/- 2%), lower fractional shortening at rest (27 +/- 1% vs 34 +/- 2%), higher end-systolic wall stress (150 +/- 18 vs 99 +/- 8 dynes/cm2 X 10(3], lower left ventricular relative wall thickness (0.26 +/- 0.01 vs 0.30 +/- 0.01), and greater end-systolic diameter (5.7 +/- 0.3 vs 4.5 +/- 0.2 cm) than patients with negative tests (p less than 0.05 for all comparisons). Among the 18 asymptomatic patients, positive tests were associated with lower resting fractional shortening, lower exercise ejection fraction, higher wall stress, and greater end-systolic diameter. These data demonstrate that a positive exercise ECG in aortic regurgitation identifies patients, even when asymptomatic, who have developed markedly abnormal left ventricular functional and geometric responses to volume load, while a negative exercise ECG identifies a subset of asymptomatic patients who are unlikely to have severe ventricular dysfunction.