Josef Korinek

Accuracy of body mass index in diagnosing obesity in the adult general population.

Background:Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown.Methods:A cross-sectional design of 13 601 subjects (age 20–79.9 years; 49% men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25% in men and>35% in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race.Results:BMI-defined obesity (⩾30 kg m−2) was present in 19.1% of men and 24.7% of women, while BF%-defined obesity was present in 43.9% of men and 52.3% of women. A BMI⩾30 had a high specificity (men=95%, 95% confidence interval (CI), 94–96 and women=99%, 95% CI, 98–100), but a poor sensitivity (men=36%, 95% CI, 35–37 and women=49%, 95% CI, 48–50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25–29.9 kg m−2), BMI failed to discriminate between BF% and lean mass in both sexes.Conclusions:The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of⩾30 kg m−2 has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.

Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality

AIMS We hypothesized that subjects with a normal body mass index (BMI), but high body fat (BF) content [normal weight obesity (NWO)], have a higher prevalence of cardiometabolic dysregulation and are at higher risk for cardiovascular (CV) mortality. METHODS AND RESULTS We analysed 6171 subjects >20 years of age from the Third National Health and Nutrition Examination Survey (NHANES III) and the NHANES III mortality study, whose BMI was within the normal range (18.5-24.9 kg/m(2)), and who underwent a complete evaluation that included body composition assessment, blood measurements, and assessment of CV risk factors. Survival information was available for >99% of the subjects after a median follow-up of 8.8 years. We divided our sample using sex-specific tertiles of BF%. The highest tertile of BF (>23.1% in men and >33.3% in women) was labelled as NWO. When compared with the low BF group, the prevalence of metabolic syndrome in subjects with NWO was four-fold higher (16.6 vs. 4.8%, P < 0.0001). Subjects with NWO also had higher prevalence of dyslipidaemia, hypertension (men), and CV disease (women). After adjustment, women with NWO showed a significant 2.2-fold increased risk for CV mortality (HR = 2.2; 95% CI, 1.03-4.67) in comparison to the low BF group. CONCLUSION Normal weight obesity, defined as the combination of normal BMI and high BF content, is associated with a high prevalence of cardiometabolic dysregulation, metabolic syndrome, and CV risk factors. In women, NWO is independently associated with increased risk for CV mortality.

Dynamic Changes of Left Ventricular Performance and Left Atrial Volume Induced by the Mueller Maneuver in Healthy Young Adults and Implications for Obstructive Sleep Apnea, Atrial Fibrillation, and Heart Failure

Using the Mueller maneuver (MM) to simulate obstructive sleep apnea (OSA), our aim was to investigate acute changes in left-sided cardiac morphologic characteristics and function which might develop with apneas occurring during sleep. Strong evidence supports a relation between OSA and both atrial fibrillation and heart failure. However, acute effects of airway obstruction on cardiac structure and function have not been well defined. In addition, it is unclear how OSA might contribute to the development of atrial fibrillation and heart failure. Echocardiography was used in healthy young adults to measure various parameters of cardiac structure and function. Subjects were studied at baseline, during, and immediately after performance of the MM and after a 10-minute recovery. Continuous heart rate, blood pressure, and pulse oximetry measurements were made. During the MM, left atrial (LA) volume index markedly decreased. Left ventricular (LV) end-systolic dimension increased in association with a decrease in LV ejection fraction. On release of the maneuver, there was a compensatory increase in blood flow to the left side of the heart, with stroke volume, ejection fraction, and cardiac output exceeding baseline. After 10 minutes of recovery, all parameters returned to baseline. In conclusion, sudden imposition of severe negative intrathoracic pressure led to an abrupt decrease in LA volume and a decrease in LV systolic performance. These changes reflected an increase in LV afterload. Repeated swings in afterload burden and chamber volumes may have implications for the future development of atrial fibrillation and heart failure.

Disparate patterns of left ventricular mechanics differentiate constrictive pericarditis from restrictive cardiomyopathy.

OBJECTIVES The purpose of this study was to compare the longitudinal, circumferential, and radial mechanics of the left ventricle (LV) in patients with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). BACKGROUND Diastolic dysfunction in CP is related to epicardial tethering and pericardial constraint, whereas in RCM it is predominantly characterized by subendocardial dysfunction. Assessment of variations in longitudinal and circumferential deformation of LV might be useful to distinguish these 2 conditions. METHODS Longitudinal, radial, and circumferential mechanics of the LV were quantified by 2-dimensional speckle tracking of B-mode cardiac ultrasound images in 26 patients with CP, 19 patients with RCM, and 21 control subjects. RESULTS In comparison with control subjects, patients with CP had significantly reduced circumferential strain (base; -16 +/- 6% vs. -9 +/- 6%; p < 0.016), torsion (3 +/- 1 degrees /cm vs. 1 +/- 1 degrees /cm; p < 0.016), and early diastolic apical untwisting velocities (E(r); 116 +/- 62 degrees /s vs. -36 +/- 50 degrees /s; p < 0.016), whereas longitudinal strains, displacement, and early diastolic velocities at the LV base (E(m)) were similar to control subjects. In contrast, patients with RCM showed significantly reduced longitudinal displacement (base; 14.7 +/- 2.5 cm vs. 9.8 +/- 2.8 cm; p < 0.016) and E(m) (-8.7 +/- 1.3 cm/s vs. -4.4 +/- 1.1 cm/s; p < 0.016), whereas circumferential strain and E(r) were similar to those of control subjects. For differentiation of CP from RCM, the area under the curve was significantly higher for E(m) in comparison with E(r) (0.97 vs. 0.76, respectively; p = 0.01). After pericardiectomy, there was a significant decrease in longitudinal early diastolic LV basal myocardial velocities (7.4 cm/s vs. 6.8 cm/s; p = 0.023). Circumferential strain, torsion, and E(r), however, remained unchanged. CONCLUSIONS Deformation of the LV is constrained in the circumferential direction in CP and in the longitudinal direction in RCM. Subsequent early diastolic recoil of LV is also attenuated in each of the 2 directions, respectively, uniquely differentiating the abnormal diastolic restoration mechanics of the LV seen in CP and RCM.

Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general population

Background Leptin could be a key regulator of C-reactive protein (CRP) levels, which serve as a marker of systemic inflammation. Both leptin and CRP are predictors of cardiovascular disease (CVD). However, the interactions between leptin and CRP, and their association with CVD, remain unclear. We therefore studied them in a large, multiethnic population.Methods We analyzed leptin and CRP levels, anthropometric variables and cardiovascular risk factor data from 6,251 participants from the Third National Health and Nutrition Examination Survey (NHANES III). Logistic regression was used to estimate the association between leptin, CRP and CVD (defined as history of myocardial infarction or stroke). Receiver operating characteristic curves were created to study the additional value of leptin and CRP for the association with CVD.Results The mean age was 44.4 ± 0.21 years (52.5% women). After adjustment for age, race, dyslipidemia, hypertension, diabetes, smoking, obesity and CRP, high levels of leptin were significantly associated with CVD in men (odds ratio 2.47, 95% CI 1.19–5.19) and in women (odds ratio 3.30, 95% CI 1.47–7.99). After adjustment for leptin, CRP was not associated with CVD. There was a significant correlation between levels of leptin and CRP (Spearman correlation ρ = 0.22 in men and ρ = 0.32 in women, both P < 0.0001). The area under the curve, representing the association between cardiovascular risk factors and CVD, increased after the addition of high levels of both leptin and CRP together.Conclusion High leptin levels are independently associated with CVD even after adjustment for CRP; elevated CRP levels are not associated with CVD after adjustment for leptin. However, increased concentrations of both leptin and CRP confer the highest risk for CVD.

Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”

Background— Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-&bgr; hydroxysteroid dehydrogenase, salt-mineralocorticoid–induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and Results— Cardiac structure and function, oxidative stress, and mineralocorticoid receptor–dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor–dependent gene transcription. Conclusions— Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor–dependent gene transcription.

Left Ventricular Mechanics in Idiopathic Dilated Cardiomyopathy: Systolic-Diastolic Coupling and Torsion

BACKGROUND In idiopathic dilated cardiomyopathy (IDC), myocardial deformational parameters and their mutual relationships remain incompletely characterized. METHODS Thirty-seven patients with IDC underwent two-dimensional speckle-tracking echocardiography (2D-STE) to assess left ventricular rotation, torsion, and longitudinal, circumferential, and radial systolic and diastolic strains and strain rates. Additionally, 2D-STE was performed in 14 controls. RESULTS All deformational parameters on 2D-STE were significantly lower in patients with IDC compared with controls. Seven patients exhibited opposite basal (positive, counterclockwise) and 11 patients exhibited opposite apical (negative, clockwise) rotation at end-systole. Circumferential, radial, and longitudinal early diastolic strain rates were correlated most strongly with the corresponding spatial components of systolic deformation. CONCLUSION In patients IDC, all torsional, systolic, and diastolic deformational parameters were decreased. Corresponding three-dimensional components of systolic and diastolic deformations were closely coupled. Considerable variation in the direction of basal and apical rotation exists in a subset of patients with IDC.

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); (n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-β and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-β pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart.

Natriuretic peptides (NPs) are cardioprotective through the activation of guanylyl cyclase (GC) receptors A and B. CD-NP, also known as cenderitide, is a novel engineered NP that was designed to uniquely serve as a first-in-class dual GC receptor agonist. Recognizing the aldosterone suppressing actions of GC-A activation and the potent inhibitory actions on collagen synthesis and fibroblast proliferation through GC-B activation, the current study was designed to establish the anti-fibrotic actions of CD-NP, administered subcutaneously, in an experimental rat model of early cardiac fibrosis induced by unilateral nephrectomy (UNX). Our results demonstrate that a two week subcutaneous infusion of CD-NP significantly suppresses left ventricular fibrosis and circulating aldosterone, while preserving both systolic and diastolic function, in UNX rats compared to vehicle treated UNX rats. Additionally we also confirmed, in vitro, that CD-NP significantly generates the second messenger, cGMP, through both the GC-A and GC-B receptors. Taken together, this novel dual GC receptor activator may represent an innovative anti-fibrotic therapeutic agent.

Delayed Onset of Subendocardial Diastolic Thinning at Rest Identifies Hypoperfused Myocardium

Background—Onset of myocardial relaxation is highly energy dependent. Perfusion and therefore energy substrate delivery are predominantly reduced in the subendocardial myocardium in the early stages of progressive ischemia. We hypothesized that delayed onset of subendocardial diastolic thinning will functionally identify regionally hypoperfused resting myocardium. Methods and Results—Progressive left anterior descending coronary artery stenosis was induced by an ameroid occluder and maintained for 1 or 2 weeks (end point) in 12 dogs. M-mode tissue Doppler images of the anterior apical and middle segments (testing region) and middle inferior segment (control region) were acquired selectively in the subendocardium and subepicardium. The time to the onset of thinning was measured with the use of tissue Doppler velocity (TOTv) and a thickness function (TOTt). At the end point in the testing region, myocardial flow was significantly lower in the subendocardial layer (P<0.05) in all animals, whereas viability staining showed preserved transmural viability in 10 dogs and thin subendocardial necrosis in 2 dogs. Both TOTv and TOTt were significantly (P<0.01) prolonged in the testing region. The mean difference between subendocardial and subepicardial TOTv values versus that in the control region identified the ischemic region, even when only dogs with hypoperfused but transmurally viable myocardium were considered (P<0.05). Systolic and diastolic myocardial velocities did not identify subendocardial hypoperfusion. Conclusions—In resting myocardium subtended to progressive coronary stenosis, a delayed onset of subendocardial thinning suggests an early stage of hypoperfusion, before the development of local wall motion abnormalities.