Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia.

OBJECTIVE: Regulation of growth hormone (GH) receptor expression and hence tissue GH sensitivity may be important for the conflicting results found in treatment studies with recombinant growth hormone in chronic heart failure (CHF). Growth hormone-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor and is closely related to measures of body composition and, specifically, to size of visceral fat tissue. Leptin, the adipocyte specific (ob) gene product, has been proposed as the signal linking adipose tissue and GHBP/GH-receptor expression. CHF has recently been shown to be a hyperleptinaemic and insulin-resistant state regardless of aetiology. This study aimed to examine the influence of leptin on GHBP in CHF patients with and without cardiac cachexia compared with healthy control subjects. METHODS: We studied 47 male patients with CHF (mean age 61+/-2 years, New York Heart Association (NYHA)-class 2.7+/-0.1, left ventricular ejection fraction (LVEF) 28+/-2%, peak oxygen consumption 16.8+/-0.9 ml/kg/min) and 21 male healthy controls of similar age. Of the CHF patients, 19 were cachectic (cCHF; non-oedematous weight loss >7.5% over at least 6 months) and 28 non-cachectic (ncCHF; similar for age and LVEF). Insulin sensitivity was assessed by an intravenous glucose tolerance test using the minimal model approach. RESULTS: Compared with healthy controls, patients had elevated levels of leptin (7.6+/-0.7 vs 4.8+/-0.7 ng/ml, P<0.05), insulin (76.2+/-8.9 vs 41.4+/-6.0 pmol/l, P<0.01), and reduced insulin sensitivity (2.43+/-0.2 vs 3.48+/-0.3 min(-1).microU.ml(-1).10(4), P<0.005) but similar GHBP levels (901+/-73 vs 903+/-95 pmol/l). Leptin levels were increased in ncCHF (9.11+/-1.0 ng/ml, P=0.001) but were not different from normal in cCHF (5.32+/-0.7 ng/ml, P>0.5). After correction for total body fat mass, both ncCHF and cCHF were hyperleptinaemic (41.8+/-3.8 and 37.9+/-0.38 vs 24.4+/-2.1 ng/ml/100 g, ANOVA P=0.001). In both patients and controls there was a direct correlation between leptin levels and GHBP (r=0.70 and r=0.71 respectively, both P<0.0001). This relationship was stronger than between GHBP and several parameters of body composition (body mass index (BMI), total and regional body fat mass or % body fat) and held true when sub-groups were tested individually (ncCHF r=0.62, P<0.001; cCHF r=0.79, P<0.0001). In multivariate regression analysis in all CHF patients, serum leptin levels emerged as the strongest predictor of GHBP, independent of age, BMI, total and regional fat mass or % body fat, fasting insulin level and insulin sensitivity. CONCLUSION: Fat mass corrected leptin levels are elevated in CHF patients with and without cachexia. Reduced total fat mass may account for lower leptin levels in cachectic CHF patients compared with non cachectic patients. Leptin strongly predicts GHBP levels in CHF regardless of its hyperleptinaemic state or severely altered body composition as in cardiac cachexia. Leptin could be the signalling link between adipose tissue and GHBP/GH receptor expression in CHF.

Wasting as an independent predictor of mortality in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is the most common life threatening autosomal recessive disorder in the white population. Wasting has long been recognised as a poor prognostic marker in CF. Whether it predicts survival independently of lung function and arterial blood gas tensions has not previously been reported. METHODS: 584 patients with CF (261 women) of mean (SD) age 21 (7) years were studied between 1985 and 1996, all of whom were being followed up in a tertiary referral centre. Lung function tests, body weight, arterial blood oxygen (PaO(2)) and carbon dioxide (PaCO(2)) tensions were measured. The weight was calculated as a percentage of the ideal body weight for age, height, and sex. RESULTS: Forced expiratory volume in one second (FEV(1)) recorded at the start of the study was 1.8 (1.0) l (52 (26)% predicted FEV(1)), PaO(2) 9.8 (1.9) kPa, PaCO(2) 5.0 (0.9) kPa, and % ideal weight 92 (18)%. During the follow up period (45 (27) months) 137 patients died (5 year survival 72%, 95% CI 67 to 73). FEV(1), % predicted FEV(1), PaO(2), % ideal weight (all p<0.0001), and PaCO(2) (p=0.04) predicted survival. In multivariate analysis, % predicted FEV(1) (p<0.0001), % ideal weight (p=0.004), and PaCO(2) (p=0.02) were independent predictors of outcome. Patients with >85% ideal body weight had a better prognosis at 5 years (cumulative survival 84%, 95% CI 79 to 89) than those with < or =85% ideal weight (survival 53%, 95% CI 45 to 62), p<0.0001. Percentage predicted FEV(1) (area under curve 0.83; 95% CI 0.78 to 0.87) and % ideal weight (area under curve 0.74; 95% CI 0.68 to 0.79) were accurate predictors of survival at 5 years follow up (receiver-operating characteristic analysis). CONCLUSIONS: Body wasting is a significant predictor of survival in patients with CF independent of lung function, arterial blood oxygen and carbon dioxide tensions.

Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance.

BACKGROUND: Chronic heart failure (CHF) is a hyperuricemic state, and capillary endothelium is the predominant site of xanthine oxidase in the vasculature. Upregulated xanthine oxidase activity (through production of toxic free radicals) may contribute to impaired regulation of vascular tone in CHF. We aimed to study the relationship between serum uric acid levels and leg vascular resistance in patients with CHF with and without cachexia and in healthy control subjects. METHODS: In 23 cachectic and 44 noncachectic patients with CHF (age, 62 +/- 1 years, mean +/- SEM) and 10 healthy control subjects (age, 68 +/- 1 years), we assessed leg resting and postischemic peak vascular resistance (calculated from mean blood pressure and leg blood flow by venous occlusion plethysmography). RESULTS: Cachectic patients, compared with noncachectic patients and control subjects, had the highest uric acid levels (612 +/- 36 vs 459 +/- 18 and 346 +/- 21 micromol/L, respectively, both P <.0001) and the lowest peak leg blood flow and vascular reactivity (reduction of leg vascular resistance from resting to postischemic conditions: 83% vs 88% and 90%, both P <.005). In all patients, postischemic vascular resistance correlated significantly and independently of age with uric acid (r = 0.61), creatinine (r = 0.47, both P <.0001), peak VO2 (r = 0.34), and New York Heart Association class (r = 0.33, both P <.01). This correlation was not present in healthy control subjects (r = -0.04, P =.9). In multivariate and stepwise regression analyses, serum uric acid emerged as the strongest predictor of peak leg vascular resistance (standardized coefficient = 0.61, P <.0001) independent of age, peak VO2, creatinine, New York Heart Association class, and diuretic dose. CONCLUSIONS: Hyperuricemia and postischemic leg vascular resistance are highest in cachectic patients with CHF, and both are directly related independent of diuretic dose and kidney function. The xanthine oxidase metabolic pathway may contribute to impaired vasodilator capacity in CHF.

Right ventricular dysfunction in adult severe cystic fibrosis.

STUDY OBJECTIVES: This study sought to assess the extent of impairment of cardiac function in adult patients with end-stage cystic fibrosis (CF) and to examine the relationship between cardiovascular abnormalities and the degree of hypoxemia and hypercapnia. DESIGN AND SETTING: A retrospective study in a tertiary cardiac and CF center. PARTICIPANTS AND INTERVENTIONS: A total of 103 adult patients with end-stage CF awaiting lung or heart and lung transplantation (mean age [+/- SD], 26+/-7 years; 54 men) underwent Doppler echocardiography and arterial blood gas analysis (mean PaO(2), 54+/-10 mm Hg; mean PaCO(2), 47+/-8 mm Hg). The findings were compared to those of 17 healthy control subjects (mean age, 24+/-7 years; 13 men) who had no history of cardiac or pulmonary disease. MEASUREMENTS AND RESULTS: All patients were in sinus rhythm with a mean tachycardia of 112+/-18 beats/min (control subjects, 76+/-16; p<0.0001) and had a cardiac output of 5.3 L/min (control subjects, 4.3 L/min; p<0.04). In the patient group, the left ventricular (LV) dimensions, systolic and diastolic function, and wall thickness were all within normal limits. The mean amplitude of long-axis excursion in patients was normal at the LV site, but that of the right ventricular (RV) free wall was significantly reduced as compared with control subjects (1.6+/-0.4 vs. 2.2+/-0.4 cm, respectively; p<0.001), which was found to correlate with the degree of hypoxemia (r = 0.63; p<0.02) and hypercapnia (r = -0.68; p<0.01). RV diastolic function, which was represented by the relative isovolumic relaxation time to cardiac cycle length, was longer in patients than in control subjects (8.7+/-4.8% vs. 5.0+/-3.0%, respectively; p<0.03). The pulmonary flow acceleration time (90+/-22 vs 121+/-34 ms, respectively; p<0.01) and the systolic stroke distance (7.0+/-2.2 vs. 10.5+/-1.9 cm/s(2); p<0.001) were both lower than normal. CONCLUSIONS: This study confirms the presence of significant RV systolic and diastolic dysfunction in the setting of consistent tachycardia and increased cardiac output in adult CF patients with severe disease. No specific LV abnormalities were detected in these patients.

Echocardiographic determinants of mortality in patients >67 years of age with chronic heart failure.

This study sought to assess the prognostic significance of echocardiographic measurements of left and right ventricular dimensions and function in patients >67 years of age with chronic congestive heart failure (CHF). This is a retrospective follow-up of elderly patients who underwent an echocardiography in the tertiary cardiac center. A total of 185 patients (131 men) aged >/=68 years (mean +/- SD 75 +/- 5) with CHF were enrolled into the study. After undergoing a detailed echocardiographic examination, all patients were followed-up for a median of 20 months (interquartile range 9 to 36). During the follow-up period 54 patients (29%) died. Left ventricular (LV) M-mode isovolumic relaxation time (IVRT), end-diastolic and end-systolic diameters, fractional shortening and mass, transmitral E:A ratio, and left atrial dimension, as well as New York Heart Association class and the age were found by Cox proportional-hazards univariate analyses to predict the outcome in these patients (all p <0.05). In multivariate analyses including these measurements, LV IVRT (p <0.04), age (p <0.03), and New York Heart Association class (p <0.001) were found to be the independent predictors of outcome. In the Kaplan-Meier analysis, patients with LV IVRT >30 ms had a better prognosis at 3 years (cumulative survival 78% [95% confidence interval 65% to 91%]) than those with LV IVRT 67 years of age with CHF. LV M-mode IVRT is among the most important independent predictors of outcome in this population.

True shape and area of proximal isovelocity surface area (PISA) when flow convergence is hemispherical in valvular regurgitation.

The proximal isovelocity surface area (PISA) method for quantifying valvular regurgitation uses an echocardiographic image with superimposed colour Doppler mapping to visualise the contours of velocity in the blood travelling towards the regurgitant orifice. The flux of blood through the regurgitant orifice is obtained as the product of the area of one of these (presumed hemispherical) contours and the speed of the blood passing through it. However, colour Doppler mapping measures the velocity component towards the echo probe (v cos theta;) rather than speed (v), so that the contours of equal Doppler velocity (isodoppler velocity contours) differ from isospeed contours. We derive the shape of the isodoppler contour surface obtainable by colour Doppler mapping, and show that its area is much less than that of the hemispherical isospeed contour. When regurgitant flux is derived from an appropriate single measure of contour dimension, an appropriate result may be obtained. However, if the true echocardiographic surface area is measured directly, the regurgitant flux will be substantially underestimated. Indeed, the conditions necessary for isodoppler velocity contours to be hemispherical are extraordinary. We should not therefore make deductions from the apparent shape for the convergence zone without considering the principles by which the image is generated. The discrepancy will assume practical significance when increased resolution of colour Doppler technology makes measurement of apparent surface area feasible. Assuming the flow contours are indeed hemispherical, a 'correction' factor of 1.45 would be required.

Relation of changes over time in ventricular size and function to those in exercise capacity in patients with chronic heart failure.

BACKGROUND: We studied the direction and magnitude of changes in left ventricular (LV) cavity size and mass over time and whether these changes were related to those in exercise performance in patients with chronic heart failure (CHF). METHODS AND RESULTS: The study group was composed of 59 patients (55 men aged 58 +/- 10 years) with CHF and LV end-diastolic diameter (EDD) >55 mm. All underwent echocardiography and a treadmill cardiopulmonary exercise test within a 4-week interval (baseline) and again after a period of >/=4 months (median of 14 months). At baseline, the group as a whole had moderate to severe LV dysfunction with an EDD of 70 +/- 9 mm, end-systolic diameter (ESD) of 60 +/- 11 mm, and LV mass of 500 +/- 200 g. The mean peak oxygen consumption (Vo (2), 18 +/- 6 mL/kg per minute) was unrelated to LV cavity size or mass. EDD increased in 37 (63%) of the patients and fell in 22 (37%) patients from the initial to the second test. The absolute magnitude of changes over time averaged 7 mm for EDD, 125 g for mass, and 6 mL/kg per minute for peak Vo(2). Changes in LV size and mass per year were significantly related to those in peak Vo(2) (r = -0.49 for EDD, r = -0.56 for ESD, and r = -0.44 for LV mass, respectively, all P <.001) and ventilatory response to exercise (r = 0.60, r = 0.58, and r = 0.72 for EDD, ESD, and LV mass; respectively, all P <.001). CONCLUSIONS: Changes over time in objective measures of LV dimensions and mass, in patients with CHF are significantly related to those in exercise capacity and respiratory efficiency.

Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure.

AIMS: This study sought to examine the predictive values of changes over time in exercise capacity and echocardiographic measurements of ventricular dimensions or function in predicting mortality in patients with chronic heart failure. METHODS AND RESULTS: Sixty-two patients with chronic heart failure (58 men, mean [+/-SD] age 60+/-10 years, mean peak oxygen consumption (VO(2)) 18.2+/- 5.9 ml. kg(-1). min(-1), mean left ventricular ejection fraction 38.9+/-15. 8%) who underwent both treadmill exercise testing and echocardiographic examination on two occasions, separated by 19+/-15 months were followed-up for a mean of 17 months (interquartile range 9-30 months). During the follow-up period, 19 patients (30%) died and three (4.8%) underwent heart transplantation. Of measurements taken at a single time-point (visit 2) exercise duration, peak VO(2), ventilatory response to exercise (VE/VCO(2)), left atrial diameter and left ventricular ejection fraction were found, by Cox proportional-hazard analysis, to predict the outcome in these patients (all P<0.05). Of the changes in parameters between visit 1 to visit 2, only changes in peak VO(2)per year (P=0.026) predicted non-transplanted survival (independent of changes in left ventricular ejection fraction and VE/VCO(2)). In Kaplan-Meier survival analysis patients with increased peak VO(2)over time (n=28) showed a better prognosis at 2 years (cumulative survival 75% [95% confidence interval: 56-95%] than those with a decrease in peak VO(2)(n=34, cumulative survival 50% [95% confidence interval: 31-68%]). CONCLUSIONS: Although single estimates of peak VO(2), VE/VCO(2)and left ventricular ejection fraction have significant prognostic importance in patients with chronic heart failure, when monitoring changes over time only peak VO(2)remains a significant predictor of outcome.

Central and peripheral components of chronic heart failure: determinants of exercise tolerance.

This study sought to determine the relationship between myocardial dysfunction and peripheral haemodynamic disorders to exercise intolerance in patients with chronic heart failure (CHF). Seventeen patients with mild to moderate CHF (peak oxygen consumption (VO2) >16 ml/min/kg) and 13 with severe CHF (peak VO2 <16 ml/min/kg) underwent invasive (Swan-Ganz) cardiopulmonary exercise testing and forearm venous occlusion plethysmography at rest and during maximal dilatation in reactive hyperaemia. There was a shift from central to peripheral haemodynamic factors limiting exercise, suggesting an increasing importance of peripheral factors in parallel to the progression of CHF. In mild to moderate CHF peak VO2 was closely related to central haemodynamics (r = 0.57 for cardiac index at rest; r = 0.76 for cardiac index at maximal workload; r = -0.54 for right arterial pressure at maximal workload; all p<0.05) and poorly correlated with peripheral haemodynamics (blood flow, vascular resistance and venous tone). In contrast, in severe CHF peak VO2 was closely related to peripheral haemodynamic factors (r = 0.79 for forearm blood flow; r = -0.82 for vascular resistance; r = -0.77 for venous tone; all p<0.05) and less to central ones. Thus, exercise tolerance of patients with mild to moderate CHF is predominantly determined by central haemodynamic factors, notably by the cardiac index. In severe CHF peripheral factors assume ever greater importance in the determining of exercise capacity.

Left ventricular remodelling: common process in patients with different primary myocardial disorders.

Currently the problem of left ventricular remodelling in the early and late stages after myocardial infarction are under intense study. Studies of the role of remodelling of the left ventricle in patients with long-term arterial hypertension have been recently initiated. The purpose of this investigation was to study whether left ventricular remodelling is common for different primary myocardial disorders. The study population consisted of 212 patients with primary myocardial lesions (121 with dilated cardiomyopathy, 45 with chronic myocarditis and 46 with prolonged damage of the myocardium with alcohol; 196 male and 16 female, mean age 42.6+/-11.3 years) and 32 age matched normal subjects (24 male and eight female). Cardiac catheterization for ventriculography and coronary angiography was performed in all subjects for detection of left ventricular haemodynamics, including chamber volume and shape at end-systole and end-diastole. Worsening of heart failure was associated with a progressive enlargement of the left ventricle, with increases in end-systolic left ventricular wall stress, that lead to increases in left ventricular muscle mass, alteration of left ventricular geometry from a more ellipsoid to a more spherical shape and a progressive decrease of relative wall thickness index that reflects inadequate enlargement of the ventricular chamber in comparison with the increase in muscle mass. This process of left ventricular remodelling was common to all the primary myocardial disorders studied. Thus, regardless of the different etiological nature, most primary myocardial disorders show a similar left ventricular remodelling process suggesting common mechanisms for the development of chronic heart failure.