The discovery of cardiac natriuretic hormones determined a radical revision of the concept of hea... more The discovery of cardiac natriuretic hormones determined a radical revision of the concept of heart function. It is now clear that the heart is not merely a pump but, through its endocrine function, exerts a nodal role in a complex information network. As a matter of fact the heart plays a key role in the regulation of circulation, salt-water homeostasis, and can exchange physiologically relevant information with other organs and systems. Highlighting the most important recent literature observations, this review discusses the inter-relationship between endocrine function of the heart and gonadal function. We have first considered the cross-talk between cardiac endocrine system and sex steroid hormones, examining the different actions of female sex steroid hormones and androgens on cardiac endocrine function, and then the action of cardiac natriuretic hormones on female and male gonadal function. Then, we have highlighted the clinical relevance of the relationships between cardiac endocrine function and sex steroid hormones in several clinical conditions associated with cardiovascular risk, focusing on mechanisms linking adipose tissue to natriuretic peptide and sex steroid hormone actions. The knowledge of the relation between cardiac endocrine function and other neurohormonal systems, including gonadal function, is crucial to explain the increased cardiovascular risk in some clinical conditions, such as obesity, arterial hypertension and metabolic syndrome.
Italian heart journal. Supplement: official journal of the Italian Federation of Cardiology
Recommendations for the clinical use of cardiac natriuretic peptides. ... Emdin M, Clerico A, Cle... more Recommendations for the clinical use of cardiac natriuretic peptides. ... Emdin M, Clerico A, Clemenza F, Galvani M, Latini R, Masson S, Mulè P, Panteghini M, Valle R, Zaninotto M, Ganau A, Mariotti R, Volpe M, Aspromonte N, Cacciatore G, Cappelletti P, L'Abbate A, Miglio F, ...
In order to study the influence of gender on circulating levels of cardiac natriuretic hormones (... more 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.
Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (H... more Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (HF), but its pathophysiological meaning is unclear. We aimed to investigate hs-Tn elevation after maximal exercise in patients with systolic HF and its neurohormonal and hemodynamic correlates: 30 patients diagnosed with systolic HF (left ventricular ejection fraction 32 ± 8%, mean ± SD), on guideline-directed medical therapy and not recognized inducible ischemia, underwent maximal cardiopulmonary stress test, with assay of plasma N-terminal proB-type natriuretic peptide (NT-proBNP), norepinephrine (NE), and hs-TnT (hs-TnT) at baseline, peak, and 1 and 4 hours after exercise. Cardiac output (CO) was measured during effort, with a rebreathing technique. The natural logarithm of the ratio between percentage (%) increase in CO and NT-proBNP (ln[CO%/NT-proBNP% increase]) was evaluated, as a noninvasive estimate of Frank-Starling adaptation to effort, with NT-proBNP variation considered as a surrogate of end-diastolic left ventricular pressure variation. Hs-TnT increased during exercise with a 4-hour peak (p = 0.001); 10 patients had hs-TnT increase >20%. Patients with Hs-TnT increase >20% were more symptomatic at rest (p = 0.039) and showed greater NE at peak exercise (p = 0.003) and less ln[CO%/NT-proBNP% increase] (p = 0.034). A lower ln[CO%/NT-proBNP% increase] correlated with greater NE at peak exercise (r = -0.430, p = 0.018). In conclusion, acute troponin elevation after maximal exercise was detected in 1/3 of this series. The association of troponin release with NE, CO, and NT-proBNP changes after effort suggests a pathophysiological link among transient hemodynamic overload, adrenergic activation, and myocardial cell damage, likely identifying a clinical subset at greater risk for HF progression.
A new model, which takes into account the circulation of blood as well as different tracee concen... more A new model, which takes into account the circulation of blood as well as different tracee concentrations in venous and arterial blood, has been developed and applied for the study of ANP, a hormone involved in sodium-water balance in physiological and pathophysiological conditions in humans. The body is considered as 2 blocks in series with recirculation. Heart and lung represent
Clinica chimica acta; international journal of clinical chemistry, Jan 30, 2015
Diagnosis of heart failure (HF) is not based on a single test, but on a combination of history, p... more Diagnosis of heart failure (HF) is not based on a single test, but on a combination of history, physical examination and appropriate investigations. For these reasons, the accuracy of diagnosis by clinical means alone is often inadequate, especially in the early, asymptomatic stages of the HF. Thus, there is an increasing interest in the development of new cardiovascular biomarkers and, consequently, a great number of laboratory tests have recently been proposed for their assay. The aim of this article is to provide a general overview on the biomarkers, recommended by international guidelines, for the diagnosis, risk stratification, and follow-up of patients with HF. Cardiac natriuretic peptides and in particular the B-type related peptides, which are considered to be the first line biomarker for HF by international guidelines, will be discussed with special emphasis.
Interest in brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proB... more Interest in brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the management of children with CHD has increased. There are, however, no current guidelines for their routine use. The aim of this review article is to provide an update on the data regarding the use of BNP/NT-proBNP in the evaluation and surgical treatment of children with CHD. BNP/NT-proBNP levels in children with CHD vary substantially according to age, laboratory assay methods, and the specific haemodynamics associated with the individual congenital heart lesion. The accuracy of BNP/NT-proBNP as supplemental markers in the integrated screening, diagnosis, management, and follow-up of CHD has been established. In particular, the use of BNP/NT-proBNP as a prognostic indicator in paediatric cardiac surgery has been widely demonstrated, as well as its role in the subsequent follow-up of surgical patients. Most of the data, however, are derived from single-centre retrospective studies using multivariable analysis; prospective, randomised clinical trials designed to evaluate the clinical utility and cost-effectiveness of routine BNP/NT-proBNP use in CHD are lacking. The results of well-designed, prospective clinical trials should assist in formulating guidelines and expert consensus recommendations for its use in patients with CHD. Finally, the use of new point-of-care testing methods that use less invasive sampling techniques - capillary blood specimens - may contribute to a more widespread use of the BNP assay, especially in neonates and infants, as well as contribute to the development of screening programmes for CHD using this biomarker.
Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP... more Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP1-98) are differently regulated in their production/secretion patterns and clearance rates; consequently, the assay for these peptides may provide complementary (or even different) pathophysiological and/or clinical information. The assay for cardiac natriuretic peptides has been utilized in clinical conditions associated with expanded fluid volume. In particular, this assay can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered a prognostic indicator of long-term survival in patients with heart failure and/or after acute myocardial infarction. Non-competitive immunometric assays (such as two-site IRMAs), even if more expensive, seem to be preferable to RIAs for routinary assay of cardiac peptide hormones because they generally have a better degree of sensitivity, accuracy, and precision.
Recently, some fully automated immunoassay methods for the measurement of BNP and NT-proBNP becam... more Recently, some fully automated immunoassay methods for the measurement of BNP and NT-proBNP became commercially available. Aim of the present study was the evaluation and comparison of the analytical performance and diagnostic accuracy of these immunoassays following the evidence-based laboratory medicine principles. We measured samples collected from 172 normal subjects and 279 consecutive patients affected by cardiac disease with different
Renin–angiotensin system, which plays an important role in the clinical evolution of heart failur... more Renin–angiotensin system, which plays an important role in the clinical evolution of heart failure, is usually evaluated by plasma renin activity (PRA) determination. PRA levels, however, depend not only on the enzyme–substrate balance, but even on the pharmacological treatment (i.e. ACE-inhibitors); therefore, angiotensin II assay might be a helpful tool in the management of these patients. Analytical performance and clinical
The clinical relevance of brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP assays as a ... more The clinical relevance of brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP assays as a diagnostic tool and prognostic marker in patients with cardiovascular diseases has recently been confirmed. However, several studies demonstrated variation of intra-individual BNP concentrations of >30% (ranging from 30% to 50%) with reference change values at the 95% confidence interval (i.e., the estimated critical difference) ranging from 99% to 130% in healthy subjects and heart failure patients. According to this estimated confidence interval, only a great variation in plasma BNP levels should be considered significant in an individual patient (for example, a decrease of >50% or an increase of more than two-fold). Many recent clinical studies have demonstrated that BNP variations below this estimated critical difference could also have clinical relevance. Like the concentration of other neuro-hormones, levels of plasma BNP fluctuate widely and rapidly along with heart rhythm and blood pressure variations in response to physiological stimuli. However, biological variation of BNP should not be interpreted strictly as random fluctuation around a homeostatic set point, as assumed by the common model used in all studies on biological variation of BNP reported in the literature. These results cannot be directly transferred to clinical practice. While awaiting more accurate studies, we suggest that variations of plasma BNP three-fold greater than the analytical imprecision should be considered as potentially relevant from a physiological and clinical point of view.
The derangement of neuro-endocrine control of circulation influences both disease evolution and r... more The derangement of neuro-endocrine control of circulation influences both disease evolution and response to treatment in patients with heart failure, but little data are available about the complex relationships between the degree of neuro-hormonal activation and clinical severity. We studied the relationships between cardiac natriuretic hormones (CNHs) and several neuro-hormones and immunological markers in a prospective cohort of 105 consecutive patients with cardiomyopathy (77 men and 28 women, mean age 66.7+/-12.4 years, range 33-89 years). We assayed the circulating levels of CNHs (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), plasma renin activity (PRA), aldosterone, cortisol, adrenaline, noradrenaline, thyroid hormones and thyroid stimulating hormone (TSH), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The concentrations of all CNHs and neurohormones were higher in patients with heart failure compared to normal subjects, except for free triiodothyronine (FT3), which was below normal values. ANP was positively related to NYHA class, IL-6, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. BNP was positively related to age, NYHA class, IL-6, TNF-alpha, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. A stepwise multiple linear regression indicated that plasma ANP depended only on ejection fraction, adrenaline and noradrenaline values, while for plasma BNP variation NYHA class contributed too. Our data confirm a progressive activation of hormonal and immunological systems in patients with heart failure. Furthermore, CNH circulating levels in heart failure are affected not only by cardiac function and disease severity, but also by activation of neuro-hormonal and stress-related cytokine systems, as well as by the thyroid hormones, even on usual medical treatment.
The discovery of cardiac natriuretic hormones determined a radical revision of the concept of hea... more The discovery of cardiac natriuretic hormones determined a radical revision of the concept of heart function. It is now clear that the heart is not merely a pump but, through its endocrine function, exerts a nodal role in a complex information network. As a matter of fact the heart plays a key role in the regulation of circulation, salt-water homeostasis, and can exchange physiologically relevant information with other organs and systems. Highlighting the most important recent literature observations, this review discusses the inter-relationship between endocrine function of the heart and gonadal function. We have first considered the cross-talk between cardiac endocrine system and sex steroid hormones, examining the different actions of female sex steroid hormones and androgens on cardiac endocrine function, and then the action of cardiac natriuretic hormones on female and male gonadal function. Then, we have highlighted the clinical relevance of the relationships between cardiac endocrine function and sex steroid hormones in several clinical conditions associated with cardiovascular risk, focusing on mechanisms linking adipose tissue to natriuretic peptide and sex steroid hormone actions. The knowledge of the relation between cardiac endocrine function and other neurohormonal systems, including gonadal function, is crucial to explain the increased cardiovascular risk in some clinical conditions, such as obesity, arterial hypertension and metabolic syndrome.
Italian heart journal. Supplement: official journal of the Italian Federation of Cardiology
Recommendations for the clinical use of cardiac natriuretic peptides. ... Emdin M, Clerico A, Cle... more Recommendations for the clinical use of cardiac natriuretic peptides. ... Emdin M, Clerico A, Clemenza F, Galvani M, Latini R, Masson S, Mulè P, Panteghini M, Valle R, Zaninotto M, Ganau A, Mariotti R, Volpe M, Aspromonte N, Cacciatore G, Cappelletti P, L'Abbate A, Miglio F, ...
In order to study the influence of gender on circulating levels of cardiac natriuretic hormones (... more 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.
Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (H... more Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (HF), but its pathophysiological meaning is unclear. We aimed to investigate hs-Tn elevation after maximal exercise in patients with systolic HF and its neurohormonal and hemodynamic correlates: 30 patients diagnosed with systolic HF (left ventricular ejection fraction 32 ± 8%, mean ± SD), on guideline-directed medical therapy and not recognized inducible ischemia, underwent maximal cardiopulmonary stress test, with assay of plasma N-terminal proB-type natriuretic peptide (NT-proBNP), norepinephrine (NE), and hs-TnT (hs-TnT) at baseline, peak, and 1 and 4 hours after exercise. Cardiac output (CO) was measured during effort, with a rebreathing technique. The natural logarithm of the ratio between percentage (%) increase in CO and NT-proBNP (ln[CO%/NT-proBNP% increase]) was evaluated, as a noninvasive estimate of Frank-Starling adaptation to effort, with NT-proBNP variation considered as a surrogate of end-diastolic left ventricular pressure variation. Hs-TnT increased during exercise with a 4-hour peak (p = 0.001); 10 patients had hs-TnT increase >20%. Patients with Hs-TnT increase >20% were more symptomatic at rest (p = 0.039) and showed greater NE at peak exercise (p = 0.003) and less ln[CO%/NT-proBNP% increase] (p = 0.034). A lower ln[CO%/NT-proBNP% increase] correlated with greater NE at peak exercise (r = -0.430, p = 0.018). In conclusion, acute troponin elevation after maximal exercise was detected in 1/3 of this series. The association of troponin release with NE, CO, and NT-proBNP changes after effort suggests a pathophysiological link among transient hemodynamic overload, adrenergic activation, and myocardial cell damage, likely identifying a clinical subset at greater risk for HF progression.
A new model, which takes into account the circulation of blood as well as different tracee concen... more A new model, which takes into account the circulation of blood as well as different tracee concentrations in venous and arterial blood, has been developed and applied for the study of ANP, a hormone involved in sodium-water balance in physiological and pathophysiological conditions in humans. The body is considered as 2 blocks in series with recirculation. Heart and lung represent
Clinica chimica acta; international journal of clinical chemistry, Jan 30, 2015
Diagnosis of heart failure (HF) is not based on a single test, but on a combination of history, p... more Diagnosis of heart failure (HF) is not based on a single test, but on a combination of history, physical examination and appropriate investigations. For these reasons, the accuracy of diagnosis by clinical means alone is often inadequate, especially in the early, asymptomatic stages of the HF. Thus, there is an increasing interest in the development of new cardiovascular biomarkers and, consequently, a great number of laboratory tests have recently been proposed for their assay. The aim of this article is to provide a general overview on the biomarkers, recommended by international guidelines, for the diagnosis, risk stratification, and follow-up of patients with HF. Cardiac natriuretic peptides and in particular the B-type related peptides, which are considered to be the first line biomarker for HF by international guidelines, will be discussed with special emphasis.
Interest in brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proB... more Interest in brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the management of children with CHD has increased. There are, however, no current guidelines for their routine use. The aim of this review article is to provide an update on the data regarding the use of BNP/NT-proBNP in the evaluation and surgical treatment of children with CHD. BNP/NT-proBNP levels in children with CHD vary substantially according to age, laboratory assay methods, and the specific haemodynamics associated with the individual congenital heart lesion. The accuracy of BNP/NT-proBNP as supplemental markers in the integrated screening, diagnosis, management, and follow-up of CHD has been established. In particular, the use of BNP/NT-proBNP as a prognostic indicator in paediatric cardiac surgery has been widely demonstrated, as well as its role in the subsequent follow-up of surgical patients. Most of the data, however, are derived from single-centre retrospective studies using multivariable analysis; prospective, randomised clinical trials designed to evaluate the clinical utility and cost-effectiveness of routine BNP/NT-proBNP use in CHD are lacking. The results of well-designed, prospective clinical trials should assist in formulating guidelines and expert consensus recommendations for its use in patients with CHD. Finally, the use of new point-of-care testing methods that use less invasive sampling techniques - capillary blood specimens - may contribute to a more widespread use of the BNP assay, especially in neonates and infants, as well as contribute to the development of screening programmes for CHD using this biomarker.
Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP... more Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP1-98) are differently regulated in their production/secretion patterns and clearance rates; consequently, the assay for these peptides may provide complementary (or even different) pathophysiological and/or clinical information. The assay for cardiac natriuretic peptides has been utilized in clinical conditions associated with expanded fluid volume. In particular, this assay can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered a prognostic indicator of long-term survival in patients with heart failure and/or after acute myocardial infarction. Non-competitive immunometric assays (such as two-site IRMAs), even if more expensive, seem to be preferable to RIAs for routinary assay of cardiac peptide hormones because they generally have a better degree of sensitivity, accuracy, and precision.
Recently, some fully automated immunoassay methods for the measurement of BNP and NT-proBNP becam... more Recently, some fully automated immunoassay methods for the measurement of BNP and NT-proBNP became commercially available. Aim of the present study was the evaluation and comparison of the analytical performance and diagnostic accuracy of these immunoassays following the evidence-based laboratory medicine principles. We measured samples collected from 172 normal subjects and 279 consecutive patients affected by cardiac disease with different
Renin–angiotensin system, which plays an important role in the clinical evolution of heart failur... more Renin–angiotensin system, which plays an important role in the clinical evolution of heart failure, is usually evaluated by plasma renin activity (PRA) determination. PRA levels, however, depend not only on the enzyme–substrate balance, but even on the pharmacological treatment (i.e. ACE-inhibitors); therefore, angiotensin II assay might be a helpful tool in the management of these patients. Analytical performance and clinical
The clinical relevance of brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP assays as a ... more The clinical relevance of brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP assays as a diagnostic tool and prognostic marker in patients with cardiovascular diseases has recently been confirmed. However, several studies demonstrated variation of intra-individual BNP concentrations of >30% (ranging from 30% to 50%) with reference change values at the 95% confidence interval (i.e., the estimated critical difference) ranging from 99% to 130% in healthy subjects and heart failure patients. According to this estimated confidence interval, only a great variation in plasma BNP levels should be considered significant in an individual patient (for example, a decrease of >50% or an increase of more than two-fold). Many recent clinical studies have demonstrated that BNP variations below this estimated critical difference could also have clinical relevance. Like the concentration of other neuro-hormones, levels of plasma BNP fluctuate widely and rapidly along with heart rhythm and blood pressure variations in response to physiological stimuli. However, biological variation of BNP should not be interpreted strictly as random fluctuation around a homeostatic set point, as assumed by the common model used in all studies on biological variation of BNP reported in the literature. These results cannot be directly transferred to clinical practice. While awaiting more accurate studies, we suggest that variations of plasma BNP three-fold greater than the analytical imprecision should be considered as potentially relevant from a physiological and clinical point of view.
The derangement of neuro-endocrine control of circulation influences both disease evolution and r... more The derangement of neuro-endocrine control of circulation influences both disease evolution and response to treatment in patients with heart failure, but little data are available about the complex relationships between the degree of neuro-hormonal activation and clinical severity. We studied the relationships between cardiac natriuretic hormones (CNHs) and several neuro-hormones and immunological markers in a prospective cohort of 105 consecutive patients with cardiomyopathy (77 men and 28 women, mean age 66.7+/-12.4 years, range 33-89 years). We assayed the circulating levels of CNHs (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), plasma renin activity (PRA), aldosterone, cortisol, adrenaline, noradrenaline, thyroid hormones and thyroid stimulating hormone (TSH), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The concentrations of all CNHs and neurohormones were higher in patients with heart failure compared to normal subjects, except for free triiodothyronine (FT3), which was below normal values. ANP was positively related to NYHA class, IL-6, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. BNP was positively related to age, NYHA class, IL-6, TNF-alpha, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. A stepwise multiple linear regression indicated that plasma ANP depended only on ejection fraction, adrenaline and noradrenaline values, while for plasma BNP variation NYHA class contributed too. Our data confirm a progressive activation of hormonal and immunological systems in patients with heart failure. Furthermore, CNH circulating levels in heart failure are affected not only by cardiac function and disease severity, but also by activation of neuro-hormonal and stress-related cytokine systems, as well as by the thyroid hormones, even on usual medical treatment.
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