Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, char... more Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) an...
Molecular autopsy is the process of investigating sudden death through genetic analysis. It is pa... more Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim’s relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the c...
Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart fai... more Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine suppleme...
The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (A... more The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned. We analyzed data from HF patients (958 patients (801 males, 84%, age 67 ± 11 years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving β-blockers (n = 777, 81%) vs. those not treated with β-blockers (n = 181, 19%). We also analyzed the role β1-selectivity and the role of daily β-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving β-blockers. 224 (23%, 54/1000 events/year), 163 (21%, 79/1000 events/year), and 61 (34%, 49/1000 events/year) even...
AimsRisk stratification in heart failure (HF) is crucial for clinical and therapeutic management.... more AimsRisk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction.Methods and resultsWe collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2‐ and 4‐year follow‐up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricula...
The use of β-blockers represents a milestone in the treatment of heart failure with reduced eject... more The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens. In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0....
European journal of internal medicine, Jan 28, 2016
Anemia is frequent in heart failure (HF), and it is associated with higher mortality. The predict... more Anemia is frequent in heart failure (HF), and it is associated with higher mortality. The predictive power of established HF prognostic parameters in anemic HF patients is unknown. Clinical, laboratory, echocardiographic and cardiopulmonary-exercise-test (CPET) data were analyzed in 3913 HF patients grouped according to hemoglobin (Hb) values. 248 (6%), 857 (22%), 2160 (55%) and 648 (17%) patients had very low (<11g/dL), low (11-12 for females, 11-13 for males), normal (12-15 for females, 13-15 for males) and high (>15) Hb, respectively. Median follow-up was 1363days (606-1883). CPETs were always performed safely. Hb was related to prognosis (Hazard ratio (HR)=0.864). No prognostic difference was observed between normal and high Hb groups. Peak oxygen consumption (VO2), ventilatory efficiency (VE/VCO2 slope), plasma sodium concentration, ejection fraction (LVEF), kidney function and Hb were independently related to prognosis in the entire population. Considering Hb groups sepa...
Background: Increased chemoreflex sensitivity to hypoxia and/or hypercapnia holds a prognostic va... more Background: Increased chemoreflex sensitivity to hypoxia and/or hypercapnia holds a prognostic value in chronic heart failure (HF), whereas its direct measurement is not widely applied, mainly due to technical constraints, We therefore aimed to evaluate whether/which clinical features, easily obtainable as part of current patient investigation, may predict altered chemoreflex sensitivity. Methods: We recruited 191 chronic patients with systolic HF (83% male, age 62±14, left ventricular ejection fraction –LVEF- 30±8%, NYHA class I-II/III: 72/28%) on optimal medical therapy. All patients underwent thorough clinical and neurohormonal evaluation, including echocardiography, cardiorespiratory monitoring and cardiopulmonary exercise testing (CPET), as well as hypoxic-normocapnic and hypercapnic-normoxic chemoreflex sensitivity evaluation by standard rebreathing technique. Variables associated with altered chemoreflex sensitivity were assessed with univariate logistic regression analysis and, due to the reduced number of events with respect to the number of variables selected, with Bayesian Model Averaging (BMA) for the estimation of multivariate models. Correlates of chemoreflex sensitivity were also assessed by random forests analysis, based on iterative computational statistics. Results: After univariate logistic regression and BMA, altered hypoxic chemoreflex sensitivity was associated with the presence of Cheyne Stokes respiration (CSR) and with the slope of ventilation to carbon dioxide production (VE/VCO2) at CPET; hypercapnic chemoreflex sensitivity was associated with VE/VCO2, LVEF, N-terminal fragment of brain natriuretic peptide (NT-proBNP) and ACE-inhibitor therapy, as a protective variable. At random forests analysis VE/VCO2 and NT-proBNP showed the strongest association with hypercapnic chemoreflex sensitivity, while CSR and VE/VCO2 showed the strongest association with hypoxic chemoreflex sensitivity. Conclusions: Reduced ventilatory efficiency predicts increased chemoreflex sensitivity to either hypoxia and hypercapnia. Altered peripheral chemoreflex is predicted by the presence of CSR, too, while abnormal central chemonsensitivityis associated with LV systolic dysfunction and neurohormonal activation. In clinical grounds, the assessment of these easily obtainable variables could help identify patients with altered chemoreflex sensitivity and thus selecting subsets suitable for targeted interventions
The described report deals with the case of a patient with diagnosis of ischemic-hypertensive car... more The described report deals with the case of a patient with diagnosis of ischemic-hypertensive cardiomyiopathy based on the history of angina and inducible myocardial ischemia with normal coronary arteries. However, after cardiac magnetic resonance, the typical amyloidotic pattern is found and the final diagnosis of multiple myeloma is made at osteomedullary biopsy.
ABSTRACT The measurement of circulating brain natriuretic peptide (BNP) and its related peptide, ... more ABSTRACT The measurement of circulating brain natriuretic peptide (BNP) and its related peptide, the N-terminal fragment of proBNP (NT-proBNP), have a high degree of diagnostic accuracy and clinical relevance both in acute and chronic heart failure (HF). However, the role of measurement of BNP/NT-proBNP in the follow-up of treated HF patients is still debated. In this chapter, authors have studied the clinical impact of B-type natriuretic peptide assay in the follow-up of patients with heart failure, and, in particular, the possible role of the measurement of its circulating levels in guiding the treatment. A relatively small number of randomized studies were designed to specifically evaluate the clinical use of BNP/NT-proBNP assay in monitoring and tailoring the medical therapy in HF patients. A meta-analysis of results reported in these studies indicate that the inefficacy to improve the mortality rate of the peptide-guided compared to the control group found in some studies, may depend on to the inability of current therapeutic strategies to modify prognosis, especially in the elderly subset of patients, who are characterized by more advanced disease and comorbidities. Further prospective and randomized clinical studies are necessary to definitively demonstrate whether BNP/NT-proBNP-guided therapy is able to significantly improve the outcome of patients with HF.
Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium,... more Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting.
Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, char... more Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) an...
Molecular autopsy is the process of investigating sudden death through genetic analysis. It is pa... more Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim’s relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the c...
Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart fai... more Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine suppleme...
The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (A... more The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned. We analyzed data from HF patients (958 patients (801 males, 84%, age 67 ± 11 years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving β-blockers (n = 777, 81%) vs. those not treated with β-blockers (n = 181, 19%). We also analyzed the role β1-selectivity and the role of daily β-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving β-blockers. 224 (23%, 54/1000 events/year), 163 (21%, 79/1000 events/year), and 61 (34%, 49/1000 events/year) even...
AimsRisk stratification in heart failure (HF) is crucial for clinical and therapeutic management.... more AimsRisk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction.Methods and resultsWe collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2‐ and 4‐year follow‐up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricula...
The use of β-blockers represents a milestone in the treatment of heart failure with reduced eject... more The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens. In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0....
European journal of internal medicine, Jan 28, 2016
Anemia is frequent in heart failure (HF), and it is associated with higher mortality. The predict... more Anemia is frequent in heart failure (HF), and it is associated with higher mortality. The predictive power of established HF prognostic parameters in anemic HF patients is unknown. Clinical, laboratory, echocardiographic and cardiopulmonary-exercise-test (CPET) data were analyzed in 3913 HF patients grouped according to hemoglobin (Hb) values. 248 (6%), 857 (22%), 2160 (55%) and 648 (17%) patients had very low (<11g/dL), low (11-12 for females, 11-13 for males), normal (12-15 for females, 13-15 for males) and high (>15) Hb, respectively. Median follow-up was 1363days (606-1883). CPETs were always performed safely. Hb was related to prognosis (Hazard ratio (HR)=0.864). No prognostic difference was observed between normal and high Hb groups. Peak oxygen consumption (VO2), ventilatory efficiency (VE/VCO2 slope), plasma sodium concentration, ejection fraction (LVEF), kidney function and Hb were independently related to prognosis in the entire population. Considering Hb groups sepa...
Background: Increased chemoreflex sensitivity to hypoxia and/or hypercapnia holds a prognostic va... more Background: Increased chemoreflex sensitivity to hypoxia and/or hypercapnia holds a prognostic value in chronic heart failure (HF), whereas its direct measurement is not widely applied, mainly due to technical constraints, We therefore aimed to evaluate whether/which clinical features, easily obtainable as part of current patient investigation, may predict altered chemoreflex sensitivity. Methods: We recruited 191 chronic patients with systolic HF (83% male, age 62±14, left ventricular ejection fraction –LVEF- 30±8%, NYHA class I-II/III: 72/28%) on optimal medical therapy. All patients underwent thorough clinical and neurohormonal evaluation, including echocardiography, cardiorespiratory monitoring and cardiopulmonary exercise testing (CPET), as well as hypoxic-normocapnic and hypercapnic-normoxic chemoreflex sensitivity evaluation by standard rebreathing technique. Variables associated with altered chemoreflex sensitivity were assessed with univariate logistic regression analysis and, due to the reduced number of events with respect to the number of variables selected, with Bayesian Model Averaging (BMA) for the estimation of multivariate models. Correlates of chemoreflex sensitivity were also assessed by random forests analysis, based on iterative computational statistics. Results: After univariate logistic regression and BMA, altered hypoxic chemoreflex sensitivity was associated with the presence of Cheyne Stokes respiration (CSR) and with the slope of ventilation to carbon dioxide production (VE/VCO2) at CPET; hypercapnic chemoreflex sensitivity was associated with VE/VCO2, LVEF, N-terminal fragment of brain natriuretic peptide (NT-proBNP) and ACE-inhibitor therapy, as a protective variable. At random forests analysis VE/VCO2 and NT-proBNP showed the strongest association with hypercapnic chemoreflex sensitivity, while CSR and VE/VCO2 showed the strongest association with hypoxic chemoreflex sensitivity. Conclusions: Reduced ventilatory efficiency predicts increased chemoreflex sensitivity to either hypoxia and hypercapnia. Altered peripheral chemoreflex is predicted by the presence of CSR, too, while abnormal central chemonsensitivityis associated with LV systolic dysfunction and neurohormonal activation. In clinical grounds, the assessment of these easily obtainable variables could help identify patients with altered chemoreflex sensitivity and thus selecting subsets suitable for targeted interventions
The described report deals with the case of a patient with diagnosis of ischemic-hypertensive car... more The described report deals with the case of a patient with diagnosis of ischemic-hypertensive cardiomyiopathy based on the history of angina and inducible myocardial ischemia with normal coronary arteries. However, after cardiac magnetic resonance, the typical amyloidotic pattern is found and the final diagnosis of multiple myeloma is made at osteomedullary biopsy.
ABSTRACT The measurement of circulating brain natriuretic peptide (BNP) and its related peptide, ... more ABSTRACT The measurement of circulating brain natriuretic peptide (BNP) and its related peptide, the N-terminal fragment of proBNP (NT-proBNP), have a high degree of diagnostic accuracy and clinical relevance both in acute and chronic heart failure (HF). However, the role of measurement of BNP/NT-proBNP in the follow-up of treated HF patients is still debated. In this chapter, authors have studied the clinical impact of B-type natriuretic peptide assay in the follow-up of patients with heart failure, and, in particular, the possible role of the measurement of its circulating levels in guiding the treatment. A relatively small number of randomized studies were designed to specifically evaluate the clinical use of BNP/NT-proBNP assay in monitoring and tailoring the medical therapy in HF patients. A meta-analysis of results reported in these studies indicate that the inefficacy to improve the mortality rate of the peptide-guided compared to the control group found in some studies, may depend on to the inability of current therapeutic strategies to modify prognosis, especially in the elderly subset of patients, who are characterized by more advanced disease and comorbidities. Further prospective and randomized clinical studies are necessary to definitively demonstrate whether BNP/NT-proBNP-guided therapy is able to significantly improve the outcome of patients with HF.
Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium,... more Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting.
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