Influence of gender on circulating cardiac natriuretic hormones in patients with heart failure.

In order to study the influence of gender on circulating levels of cardiac natriuretic hormones (CNHs) in heart failure, we measured the plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by means of highly sensitive and specific IRMA methods in 239 consecutive patients (age 64.7 +/- 11.6 years, range 21-89 years; 170 men and 69 women) with cardiomyopathy. There was different response of CNH according to gender in patients with heart failure, as indicated by the ratio between the individual CNH values of patients and the gender-specific cut-off values. Indeed, the mean ratio for ANP found in men (3.6 +/- 3.6) was significantly higher (p = 0.0075) than that found in women (2.4 +/- 2.1). The mean ratio for BNP was on average 2.3 fold higher (15.9 +/- 27.1 in men and 6.9 +/- 6.8 in women, p = 0.0084). Moreover, age, ejection fraction, and disease severity independently and significantly contributed to regression with both ANP (R = 0.612, F = 39.969, p < 0.0001) and BNP (R = 0.656, F = 49.957, p < 0.0001) values, while gender did not. In conclusion, our study suggests a different, gender-specific activation of the CNH system in this clinical condition, although age, ejection fraction and disease severity seem to be more powerful predictors than gender of circulating levels of ANP and BNP in patients with heart failure.     

How to take arms against central apneas in heart failure

Introduction Despite being a risk mediator in several observational studies, central apneas are currently orphan of treatment in heart failure. After the neutral effects on survival of two randomized controlled trials (RCTs) based on the use of positive airway pressure (the CANPAP and SERVE-HF trials), two alternative hypotheses have been formulated:

1) Periodic breathing/Cheyne-Stokes respiration (PB/CSR) in HF is protective. Indeed, the Naughton’s hypothesis assumes that hyperventilation leads to increased cardiac output, lung volume, oxygen storage and reduced muscle sympathetic nerve activity, while central apnea to respiratory muscle rest and hypoxia-induced erythropoiesis.

2) The use of positive airway pressure is just a wrong treatment for PB/CSR. If this is the case, the search for novel potential alternative treatment approaches is mandatory in HF.

Areas covered This review will focus on the crucial issue of whether PB/CSR should be treated or not in HF, first by outlining the ideal design of pathophysiological studies to test the Naughton’s hypothesis and second by summarizing the treatment strategies so far proposed for PB/CSR in HF and identifying the most promising options to be tested in future RCTs.

Expert commentary It is likely that PB/CSR may be compensatory in some cases, but after a certain threshold (to be defined) it becomes maladaptive with negative prognostic meaning in HF. The development of a pathophysiologically based treatment targeting feedback resetting and neurohormonal activation underlying PB/CSR is likely to be the best option to obtain survival benefits in HF.     

Natriuretic peptide testing in primary care patients

The evaluation of cardiac endocrine function by means of automated robust assays has permitted the introduction of a cheap and powerful clinical tool. Plasma concentration of B-type-related natriuretic peptides is a marker of either hemodynamic or neurohormonal stress on the heart and has been validated within the diagnostic and prognostic domain in patients with suspected or ascertained heart failure, mostly in the in-hospital setting. Evidence is growing, supporting an out-of-hospital use, namely in primary care. Its implementation in this setting in screening programs and diagnostic algorithms might contribute to decrease the apparent disparity between the general practitioner and the specialist approach to disease management.     

C-type natriuretic peptide expression in patients with chronic heart failure: effects of aerobic training.

BACKGROUND: C-type natriuretic peptide (CNP) is structurally related to cardiac natriuretic peptides and is currently considered as an endothelium-derived hyperpolarizing factor. Endothelial dysfunction, commonly observed in chronic heart failure (HF) patients is positively affected by physical training. METHODS: To evaluate the effect of aerobic physical training on the expression of CNP, 90 HF patients on optimal pharmacological treatment (age 62+/-2 years, mean+/-SEM), randomly assigned in a 3 : 1 ratio to either control group (C, 19 patients) or home-based aerobic exercise-training program group (T, 71 patients), completed the protocol. Plasma assay of CNP, brain natriuretic peptide or B-type natriuretic peptide (BNP), and norepinephrine; echocardiogram; and cardiopulmonary-stress test were performed in all patients at enrollment and after 9 months. RESULTS: At baseline, in both groups, CNP plasma level was significantly related to BNP (R=0.50), ejection fraction (R=0.43), and peak oxygen uptake (VO2, R=0.43, all P<0.001). After 9 months, trained patients showed an improvement in peak VO2 (P<0.001) and ejection fraction (P<0.05), whereas norepinephrine (P<0.05), BNP (P<0.001), and CNP (P<0.001) decreased. No changes occurred in group C. In group T, the decrease in CNP was significantly related to the increase in peak VO2 (R=0.31, P<0.01), and the relation between CNP and BNP was preserved at the end of the program (R=0.41, P<0.001). CONCLUSION: Clinical and functional improvement after physical training in HF patients is associated with a decrease in adrenergic activation and in both CNP and BNP concentration. Changes in CNP plasma concentration after physical training might reflect an improvement in endothelial function.     

Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure

BACKGROUND: Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Neuro-hormonal activation is a hallmark of HF and influences its clinical evolution. AIM: To evaluate the relationship between neuro-hormonal activation, exercise capacity and ventilatory efficiency. METHODS AND RESULTS: 154 HF patients (127 males, 62 +/- 1 years) underwent cardiopulmonary exercise testing and resting blood sampling for assay of plasma brain natriuretic peptide (BNP), NT-proBNP, norepinephrine, epinephrine, aldosterone and plasma renin activity (PRA). BNP and NT-proBNP levels correlated with peak oxygen consumption (VO2) (both R = -0.53, p < 0.001), VE/VCO2 slope (R = 0.56; p < 0.001 and R = 0.58; p < 0.001, respectively) and maximum workload (R = -0.49; p < 0.001 and R = -0.47; p < 0.001, respectively). Norepinephrine correlated slightly less with peak VO2 (R = -0.38, p < 0.001), VE/VCO2 (R = 0.45; p < 0.001) and maximum workload (R = -0.35; p < 0.001). There was a significant inverse correlation between left ventricular ejection fraction and BNP (R = -0.48, p < 0.001), NT-proBNP (R = -0.42; p < 0.001) and norepinephrine (R = -0.43; p < 0.001). Weaker correlations were found for PRA, exercise parameters and ejection fraction. ROC curves showed that BNP was able to identify patients with peak VO2 < 14 ml/min/kg (cut-off 98 pg/ml, AUC 0.775) and a VE/VCO2 > 35 (cut-off 183 pg/ml, AUC 0.797), as well as NT-proBNP (cut-off 537 pg/ml, AUC 0.799 and cut-off 1010 pg/ml, AUC 0.768, respectively) and norepinephrine (cut-off 454 pg/ml, AUC 0.716 and cut-off 575 pg/ml, AUC 0.783, respectively). CONCLUSION: Haemodynamic impairment (as indicated by BNP and NT-proBNP plasma values) and sympathetic activation predict exercise capacity and ventilatory efficiency in HF patients.     

Beta-lipoprotein- and LDL-associated serum gamma-glutamyltransferase in patients with coronary atherosclerosis

Elevation of serum gamma-glutamyltransferase (GGT) activity is a risk factor for myocardial infarction and stroke. GGT activity can catalyze the oxidation of low-density lipoprotein (LDL), a process involved in the pathogenesis of atherosclerosis. Serum GGT is partially adsorbed onto circulating LDL, and catalytically active GGT has been found within atherosclerotic plaques, colocalizing with oxidized LDL and foam cells. We investigated the the nature of the LDL-associated GGT, the degree of correlation between total serum GGT levels and beta-lipoprotein (beta-LP)-associated GGT, and whether this association is altered in subjects with coronary artery disease (CAD). LDL-bound GGT showed an entire, amphiphilic heavy chain, but the association was easily lost during LDL purification by affinity chromatography. When the activity of GGT associated with polycation-precipitated beta-lipoproteins was assayed, an identical immunoreactive GGT was found in Western blot, and a statistically significant linear correlation was found between total serum GGT levels and the corresponding beta-LP-bound activities (p<0.0001) in controls and patients with CAD. Nevertheless, subjects with CAD presented a lower ratio of beta-LP-bound GGT to total serum GGT respect to controls (p<0.05) and healthy subjects with elevated serum GGT (p<0.01). In addition, a relative decrease of total serum GGT was observed in CAD subjects of older age as compared to younger ones (p<0.005).     

Abnormal ventricular repolarization in hypertensive patients: role of sympatho-vagal imbalance and left ventricular hypertrophy

BACKGROUND: An increased risk for life-threatening arrhythmias and sudden death has been observed in hypertensive patients, associated with either left ventricular hypertrophy (LVH) or prolonged QT interval. To investigate the influence of autonomic imbalance and LVH on QT interval in hypertensive patients, we compared two different models of LVH: hypertension and endurance physical training. METHODS: Forty-seven untreated subjects affected by essential hypertension and 35 endurance runners, with a similar degree of LVH, were enrolled into the study. All subjects underwent 24-h ambulatory ECG recording and morning blood sampling for catecholamines. Heart rate variability was evaluated by spectral analysis and a computerized algorithm was used to measure the QT interval; QTc was then computed by the Bazett's formula. Left ventricular mass index (LVMI) was assessed by echocardiogram. RESULTS: No difference in LVMI was found between hypertensive patients and athletes. Athletes showed lower heart rate (64 +/- 1 vs. 75 +/- 1 bpm, p<0.001, mean +/- S.E.M.) and shorter QTc (401 +/- 3 vs. 434 +/- 4 ms, p<0.001) than hypertensive patients throughout the 24-h period. Athletes showed a higher vagal drive compared to hypertensive patients as suggested by bradycardia and higher values of vagal indices, which negatively correlated with QTc. Plasma norepinephrine was significantly lower in athletes than in hypertensive patients (p<0.05) and positively correlated with QTc. Conclusion: Despite similar degrees of LVH, hypertensive patients show QTc lengthening, as compared to athletes. Heart rate variability and plasma norepinephrine levels suggest sympathetic predominance in hypertensive patients, which could contribute to abnormal ventricular repolarization, thus identifying patients with an increased arrhythmic risk.     

Effects of hagfish insulin in the atlantic hagfish, Myxine glutinosa. The in vivo metabolism of [14C]glucose and [14C]leucine and studies on starvation and glucose-loading

In hagfish, starved for 1 month at 4–6°, blood glucose decreased (1.9 to 0.8 mM) and serum insulin values diminished (2.2 to 1.1 nM). More than 90% of the glycogen in the liver and skeletal muscle was consumed, whereas protein and triglyceride contents were far more stable. The serum levels of amino nitrogen, triglycerides, and free fatty acids were all decreased after starvation. The results indicate that skeletal muscle glycogen was the prime source of energy. In starved hagfish, hagfish insulin (0.1 μg/g body weight) induced an approximate twofold stimulation of the synthesis of glycogen, protein, and neutral lipids from [¹⁴C]glucose after 33 hr at 4–6°. Most of the incorporation was detected in muscle glycogen. No insulin effects were seen in the liver. In analogous studies with [¹⁴C]leucine, hagfish insulin likewise stimulated the synthesis of glycogen and protein in muscle and protein synthesis in the liver. Despite the evidence of insulin-stimulated syntheses, the total glycogen and protein contents in muscle and liver were unaltered after 33 hr. Likewise, no insulin effects were seen on blood glucose, amino nitrogen, triglycerides, or free fatty acids. Only about 10% of the radioactive dose was incorporated into the muscle and liver, and the metabolic effects of insulin contributed to only about half of this fraction. Glucose-loading increased the serum insulin value from 0.7 to 1.9 nM. Pretreatment of hagfish with a mixture of glucose and amino acids for 3 days before and after injection of the above isotopes resulted in an increase of the serum insulin values. These endogenously elevated insulin levels were sufficient to stimulate the incorporation of the label into muscle glycogen and protein. The stimulations were similar to those obtained in experiments with exogenous insulin. It was concluded that the physiological role of insulin in skeletal muscle was similar to what has been observed in higher animals although the quantitative effects of insulin in the hagfish appeared smaller than in higher vertebrates.     

C-type natriuretic peptide plasma levels increase in patients with chronic heart failure as a function of clinical severity

BACKGROUND: [corrected] C-type natriuretic peptide (CNP), secreted by the endothelium and the heart, is structurally related to atrial and brain natriuretic peptides, but its clinical significance in chronic heart failure (CHF) is controversial. AIM: To investigate the role of CNP in CHF, plasma CNP levels were determined in a prospective series of 133 patients with CHF (age 64 +/- 1 years, left ventricular ejection fraction (EF), 31.5 +/- 0.7%, mean +/-S.E.M.) and in 21 age-matched healthy subjects. METHODS AND RESULTS: CNP was measured by a radioimmunoassay (sensitivity: 0.41+/-0.009 pg/tube) after a preliminary solid-phase extraction. Plasma level of CNP in healthy subjects was 2.7 +/- 0.2 pg/ml and significantly increased in CHF, as a function of clinical severity: 4.9 +/- 0.7 pg/ml in NYHA class I; 7.0 +/- 0.4 pg/ml in class II (p < 0.001 vs. controls); 9.6 +/- 0.7 pg/ml in class III (p < 0.001 vs. controls and class I and II), and 11.8 +/- 2.0 pg/ml in class IV (p < 0.001 vs. controls, class I and II; Fisher's test after ANOVA). A significant relation was also found between CNP plasma levels and EF (R = 0.40, p < 0.001). CONCLUSION: Plasma CNP elevation is related to clinical and functional disease severity. These findings suggest a pathophysiological role for this peptide that, for its vasorelaxing activity, could influence the endothelial vasomotor response in CHF.