Galectin-3 Is Associated With Stage B Metabolic Heart Disease and Pulmonary Hypertension in Young Obese Patients.

Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese patients would help identify high-risk individuals for heart failure prevention strategies. We assessed the predictive value of GAL3 (galectin-3), FSTL3 (follistatin-like 3 peptide), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) to identify stage B MHD in young obese participants free of clinically evident cardiovascular disease. Methods and Results Asymptomatic obese patients (n=250) and non-obese controls (n=21) underwent echocardiographic cardiac phenotyping. Obese patients were classified as MHD positive ( MHD - POS ; n=94) if they had abnormal diastolic function or left ventricular hypertrophy and had estimated pulmonary artery systolic pressure ≥35 mm Hg. Obese patients without such abnormalities were classified as MHD negative (MHD-NEG; n=52). Serum biomarkers timed with echocardiography. MHD - POS and MHD-NEG individuals were similarly obese, but MHD - POS patients were older, with more diabetes mellitus and metabolic syndrome. Right ventricular coupling was worse in MHD - POS patients ( P<0.001). GAL 3 levels were higher in MHD - POS versus MHD -NEG patients (7.7±2.3 versus 6.3±1.9 ng/mL, respectively; P<0.001). Both GAL 3 and FSTL 3 levels correlated with diastolic dysfunction and increased pulmonary artery systolic pressure but not with left ventricular mass. In multivariate models including all 3 biomarkers, only GAL 3 remained associated with MHD (odds ratio: 1.30; 95% CI , 1.01-1.68; P=0.04). Conclusions In young obese individuals without known cardiovascular disease, GAL 3 is associated with the presence of preclinical MHD . GAL 3 may be useful in screening for preclinical MHD and identifying individuals with increased risk of progression to obesity-related heart failure with preserved ejection fraction.

Assessing the safety of anthrax immunization in US Army aircrew members via physical examination.

OBJECTIVE: Anthrax in weaponized form is the bioterrorism agent of most concern. Questions raised about the safety of the anthrax vaccine can be addressed by comparing immunized and unimmunized people in population-based studies. METHODS: A retrospective evaluation of data from periodic physical examinations collected on anthrax-immunized and -unimmunized US Army aircrew members between 1998 and 2005 was performed to evaluate the safety of anthrax immunization. Mean changes in variables found on physical examination and laboratory analysis were compared by use of t tests. Multiple linear regression predicted change in outcome from baseline characteristics. RESULTS: We compared 6,820 immunized subjects and 4,145 unimmunized controls based on US Army aircrew physical examination and screening laboratory tests. No association between anthrax immunization and a clinically relevant change in a tested physiologic parameter was detected. CONCLUSIONS: No attributable risk of anthrax immunization was observed in this group of Army aircrew members.

Preclinical Alterations in Myocardial Microstructure in People with Metabolic Syndrome.

OBJECTIVE: Metabolic syndrome (MetS) can lead to myocardial fibrosis, diastolic dysfunction, and eventual heart failure. This study evaluated alterations in myocardial microstructure in people with MetS by using a novel algorithm to characterize ultrasonic signal intensity variation. METHODS: Among 254 participants without existing cardiovascular disease (mean age 42 ± 11 years, 75% women), there were 162 with MetS, 47 with obesity without MetS, and 45 nonobese controls. Standard echocardiography was performed, and a novel validated computational algorithm was used to investigate myocardial microstructure based on sonographic signal intensity and distribution. The signal intensity coefficient (SIC [left ventricular microstructure]) was examined. RESULTS: The SIC was significantly higher in people with MetS compared with people with (P < 0.001) and without obesity (P = 0.04), even after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, and the ratio of triglyceride (TG) to high-density lipoprotein (HDL) cholesterol (P < 0.05 for all). Clinical correlates of SIC included TG concentrations (r = 0.21, P = 0.0007) and the TG/HDL ratio (r = 0.2, P = 0.001). CONCLUSIONS: This study's findings suggest that preclinical MetS and dyslipidemia in particular are associated with altered myocardial signal intensity variation. Future studies are needed to determine whether the SIC may help detect subclinical diseases in people with metabolic disease, with the ultimate goal of targeting preventive efforts.

Preclinical Systolic and Diastolic Dysfunctions in Metabolically Healthy and Unhealthy Obese Individuals.

BACKGROUND: Despite the substantial overlap of obesity and metabolic disease, there is heterogeneity with respect to cardiovascular risk. We sought to investigate preclinical differences in systolic and diastolic function in obesity, and specifically compare obese individuals with and without metabolic syndrome (MS). METHODS AND RESULTS: Obese individuals without cardiac disease with (OB/MS+, n=124) and without (OB/MS-, n=37) MS were compared with nonobese controls (n=29). Diastolic function was assessed by transmitral and tissue Doppler. Global longitudinal strain (LS) and time-based dyssynchrony were assessed by speckle tracking. Both OB/MS- and OB/MS+ groups had similar ejection fraction but worse systolic mechanics as assessed by LS and dyssynchrony when compared with nonobese controls. Specifically, OB/MS- had 2.5% lower LS (SE, 0.7%; P=0.001 in multivariable-adjusted analyses) and 10.8 ms greater dyssynchrony (SE, 3.3 ms; P=0.002), and OB/MS+ had 1.0% lower LS (SE, 0.3%; P<0.001) and 7.8 ms greater dyssynchrony (SE, 1.5 ms; P<0.001) when compared with controls. Obesity was associated with impaired diastolic function regardless of MS status, as evidenced by greater left atrial diameter and left ventricular mass although diastolic dysfunction was more pronounced in OB/MS+ than in OB/MS- individuals. CONCLUSIONS: Obesity is associated with subclinical differences in both systolic and diastolic function regardless of the presence or absence of MS although MS seems to be associated with worse diastolic dysfunction. When compared with controls, metabolically healthy obese had lower LS, greater dyssynchrony, and early diastolic dysfunction, supporting the notion that obesity per se may have adverse cardiovascular effects regardless of metabolic disease.

Impaired right ventricular hemodynamics indicate preclinical pulmonary hypertension in patients with metabolic syndrome.

BACKGROUND: Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease. METHODS AND RESULTS: A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m(2)), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e' (right ventricular diastolic function parameter), shorter PAAT, shorter ejection time, and larger pulmonary artery diameter compared with controls (P<0.05 for all). Estimated pulmonary artery systolic pressure based on PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls (P for ANOVA <0.0001). After adjustment for age, sex, hypertension, diabetes, body mass index, and triglycerides, MetS remained associated with a 20-ms-shorter PAAT (ß=-20.4, SE=6.5, P=0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea. CONCLUSIONS: MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.

Preclinical left ventricular diastolic dysfunction in metabolic syndrome.

Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic dysfunction can occur independent of LV hypertrophy in MS. We recruited 90 consecutive participants with MS and without cardiovascular disease (mean age 46 years, 78% women) and 26 controls (no risk factors for MS; mean age 43 years, 65% women). Participants underwent echocardiography with tissue Doppler imaging. In age- and gender-adjusted analyses, MS was associated with higher left atrial (LA) diameter, higher LV mass, lower E/A ratio, and lower mean e' (p <0.001 for all). These associations remained significant after further adjusting for blood pressure, antihypertensive medication use, and body mass index. After adjusting for LV mass, MS remained independently associated with higher LA diameter, lower E/A ratio, and lower mean e' (p ≤0.01 for all). Specifically, subjects with MS had a 1.8 cm/s lower mean e' compared with controls (p = 0.01). Notably, differences in mean e' between those with and without MS were more pronounced at younger ages (p for interaction = 0.003). In conclusion, MS was associated with preclinical LV diastolic dysfunction independent of LV mass, as reflected by higher LA diameter, lower E/A ratio, and lower mean e'. This suggests that MS can lead to the development of diastolic dysfunction through mechanisms independent of hypertrophy. Differences in diastolic function were more pronounced at younger ages, highlighting the potential importance of early risk factor modification and preventive strategies in MS.

Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure.

BACKGROUND: Galectin-3 (GAL-3), a ß-galactoside-binding protein, is a new clinical biomarker believed to reflect cardiac remodeling/fibrosis in patients with heart failure (HF). Plasma GAL-3 is inversely related to renal function. It is not known whether the relationship between renal function and GAL-3 is influenced by clinical decompensation, type of HF, or the presence or absence of clinical HF. METHODS AND RESULTS: Patients were prospectively categorized as having acute decompensated HF or stable HF on the basis of clinical status and as having HF with reduced left ventricular ejection fraction or HF with preserved left ventricular ejection fraction. Plasma GAL-3 was measured by enzyme-linked immunosorbent assay in patients with HF (n=75), control patients without HF (n=32), and control patients without HF with moderate renal insufficiency (n=12). Compared to controls without HF (14±4 ng/mL), GAL-3 was higher in patients with both acute decompensated HF (23±11 ng/mL) and stable HF (22±10 ng/mL) (P<0.001 versus controls for both) but did not differ between acute decompensated HF and stable HF (P=0.75). Likewise, GAL-3 was elevated in both HF with preserved left ventricular ejection fraction (23±9 ng/mL) and HF with reduced left ventricular ejection fraction (22±11 ng/mL) (P<0.001 versus controls for both) but did not differ between HF with preserved ejection fraction and HF with reduced ejection fraction (P=0.37). GAL-3 correlated strongly with estimated glomerular filtration rate, both in patients with HF (r=-0.75, P<0.001) and in patients without HF (r=-0.82, P<0.001), and this relationship was unaffected by the presence or absence of clinical HF. CONCLUSIONS: Plasma GAL-3 is inversely related to renal function in patients with and without clinical HF. Concentrations of plasma GAL-3 do not seem to depend on the level of compensation or type of HF. Furthermore, the relationship between GAL-3 and renal function seems to be affected little or not at all by the presence or absence of clinical HF.

The role of exercise training in heart failure.

Exercise training in patients with systolic heart failure (HF) is an accepted adjunct to an evidence-based management program. This review describes the pathophysiologic features that are thought to be responsible for the exercise intolerance experienced in the HF patient. Significant research has expanded our appreciation of the interplay of hemodynamic, ventilatory, and skeletal myopathic processes in this common, chronic condition. Randomized, controlled exercise trials designed to measure endothelial function, inflammatory markers, sympathetic neural activation, and skeletal muscle metabolism and structure have further defined the pathophysiology, documented the impact of exercise training on these processes, and confirmed the benefit of this therapy. Consistent with prior clinical research and patient experience are the recently published results of the HF-ACTION (Heart Failure-A Controlled Trial Investigating Outcomes of exercise TraiNing), which demonstrated a modest improvement in exercise capacity, reduction of symptoms, and improved self-reported measures of quality of life without adverse events. Consideration is given in this review to the benefits of variable intensity programs and the addition of resistance exercise to a standard aerobic prescription. Despite increasing validation of the role exercise training plays in the modification of exercise intolerance, challenges remain in its routine therapeutic application, including acceptance and use as an adjunctive intervention in the management of the patient with HF, limited insurance coverage for HF patients in cardiac rehabilitation, tailoring of exercise programs to best address the needs of subgroups of patients, and improved short- and long-term adherence to exercise training and a physically active lifestyle.