Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction.

BACKGROUND: Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF). METHODS: Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death. RESULTS: Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995-5666 vs 575 ng/L, 205-1714; PRA 1.7 ng/mL/h, 0.4-5.6 vs 0.6 ng/mL/h, 0.2-2.6; aldosterone 153 ng/L, 85-246 vs 113 ng/L, 72-177; norepinephrine 517 ng/L, 343-844 vs 430 ng/L, 259-624; all p < 0.001, epinephrine 31 ng/L, 10-63 vs 25 ng/L, 10-44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044). CONCLUSIONS: Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population.

NT-proBNP prognostic value is maintained in elderly and very elderly patients with chronic systolic heart failure.

BACKGROUND: Circulating concentrations of N-terminal fragment of the prohormone of brain natriuretic peptide (NT-proBNP) are influenced by age and common age-related comorbidities, such as renal dysfunction. Therefore, utility of NT-proBNP for prediction of prognosis in the aged has been questioned. We aimed to investigate the prognostic value of NT-proBNP across age classes in a cohort of patients with chronic systolic HF. METHODS AND RESULTS: We enrolled 2364 consecutive outpatients with HF and left ventricular ejection fraction ≤50%. Patients were classified according to age quartiles, and a very elderly subgroup was identified, aged ≥85 years. After baseline assessment (including NT-proBNP testing), patients were followed-up for the composite of cardiovascular death, heart transplantation or ventricular assistance device implantation (primary outcome) and for all-cause death (secondary outcome). Patients in the fourth quartile (Q4, age ≥ 77 years, n = 638) and in the very elderly subgroup (age ≥ 85 years, n = 153), had higher NT-proBNP (p < .001 vs Q1). NT-proBNP was independently associated with primary and secondary outcome at 1- and 5-years follow-up in the whole population, as well as in Q4 and in the very elderly subgroup (all p < .05). Compared to the whole population, Q4 and very elderly had higher NT-proBNP cut-off for prediction of 1-year primary (4188 and 9729 ng/l, respectively vs 3710 ng/l) and secondary outcome (4296 and 7634 ng/l, respectively vs 3056 ng/l). CONCLUSIONS: NT-proBNP predicts mortality in elderly and very elderly patients with chronic systolic HF, both at mid- and long-term follow-up. Higher NT-proBNP prognostic cut-off should be considered in the aged HF population.

Glycosylated haemoglobin is associated with neurohormonal activation and poor outcome in chronic heart failure patients with mild left ventricular systolic dysfunction.

AIMS: We aimed to evaluate the impact of glycometabolic imbalance as assessed by glycosylated haemoglobin [HbA(1c)] on neurohormonal activation and outcome in chronic heart failure (CHF). METHODS AND RESULTS: Nine hundred and twenty CHF patients (65 ±â€Š12 years, left ventricular ejection fraction 33 ±â€Š10%, 29% diabetic patients) underwent a thorough humoral and clinical characterization, including HbA(1c), and were then followed up for the endpoint of cardiac death. In the whole population, diagnosis of diabetes resulted in no difference in neurohormonal or echocardiographic data, or in outcome. Conversely, the diabetic patients with HbA(1c) above 7% showed, in comparison to both diabetic patients with HbA(1c) below 7% and non-diabetic individuals, higher plasma renin activity (1.81, 0.48-5.68 vs. 1.23, 0.43-2.8 and 1.29, 0.44-5 ng/ml/h, respectively; P < 0.01 for both), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) (1602, 826-3498 vs. 1022, 500-3543 and 1134, 455-3545 ng/l, respectively; P < 0.01 for both) and worse symptoms with a higher rate of cardiac mortality vs. both diabetic patients with HbA1(c) below 7% and non-diabetic individuals (P < 0.05 for both). In the left ventricular ejection fraction 38-50% tertile (mild left ventricular dysfunction), elevated HbA(1c) was associated with higher NT-pro-BNP and PRA (P < 0.01), and, alongside NT-pro-BNP, resulted the only independent predictor of outcome beyond diagnosis of diabetes. HbA(1c) failed to show up differences in neuroendocrine activation or in outcome in moderate and severe left ventricular dysfunction tertiles. CONCLUSION: Glycometabolic imbalance, as represented by HbA(1c), is associated with neurohormonal activation and poor prognosis in CHF patients, beyond diabetes. The impact of metabolic derangement on prognosis appears greater at the early stages of CHF, when it might exacerbate neurohormonal activation.

Conventional insulin vs insulin infusion therapy in acute coronary syndrome diabetic patients.

AIM: To evaluate the impact on glucose variability (GLUCV) of an nurse-implemented insulin infusion protocol when compared with a conventional insulin treatment during the day-to-day clinical activity. METHODS: We enrolled 44 type 2 diabetic patients (n = 32 males; n = 12 females) with acute coronary syndrome (ACS) and randomy assigned to standard a subcutaneous insulin treatment (n = 23) or a nurse-implemented continuous intravenous insulin infusion protocol (n = 21). We utilized some parameters of GLUCV representing well-known surrogate markers of prognosis, i.e., glucose standard deviation (SD), the mean daily δ glucose (mean of daily difference between maximum and minimum glucose), and the coefficient of variation (CV) of glucose, expressed as percent glucose (SD)/glucose (mean). RESULTS: At the admission, first fasting blood glucose, pharmacological treatments (insulin and/or anti-diabetic drugs) prior to entering the study and basal glycated hemoglobin (HbA1c) were observed in the two groups treated with subcutaneous or intravenous insulin infusion, respectively. When compared with patients submitted to standard therapy, insulin-infused patients showed both increased first 24-h (median 6.9 mmol/L vs 5.7 mmol/L P < 0.045) and overall hospitalization δ glucose (median 10.9 mmol/L vs 9.3 mmol/L, P < 0.028), with a tendency to a significant increase in first 24-h glycaemic CV (23.1% vs 19.6%, P < 0.053). Severe hypoglycaemia was rare (14.3%), and it was observed only in 3 patients receiving insulin infusion therapy. HbA1c values measured during hospitalization and 3 mo after discharge did not differ in the two groups of treatment. CONCLUSION: Our pilot data suggest that no real benefit in terms of GLUCV is observed when routinely managing blood glucose by insulin infusion therapy in type 2 diabetic ACS hospitalized patients in respect to conventional insulin treatment.

Prognostic value of plasma renin activity in heart failure.

The prognostic role of specific biomarkers of the renin-angiotensin-aldosterone system and sympathetic activation pathways in heart failure has never been investigated in populations with current evidence-weighted treatment. To establish whether the plasma renin activity (PRA), among several neurohormonal biomarkers, is able to predict cardiac events in a population of patients with heart failure on up-to-date treatment, we selected 996 consecutive patients with systolic left ventricular dysfunction (ejection fraction <50%, mean age 65 ± 13 years), who underwent a complete clinical and humoral characterization and were then followed up (median 36 months, range 0 to 72) for cardiac death and appropriate implantable cardioverter device shock. We recorded 170 cardiac deaths and 27 shocks. On Cox multivariate analysis, only ejection fraction (hazard ratio 0.962, 95% confidence interval 0.938 to 0.986), N-terminal pro-brain natriuretic peptide (NT-proBNP; hazard ratio 1.729, 95% confidence interval 1.383 to 2.161) and PRA (hazard ratio 1.201, 95% confidence interval 1.024 to 1.408) were independent predictors of cardiac death. Receiver operating characteristic curve analysis identified a cutoff value for PRA of 2.30 ng/ml/hour that best predicted cardiac mortality. Independent predictors of PRA were ejection fraction, functional class, sodium, potassium, NT-proBNP, norepinephrine, aldosterone, C-reactive protein, and medical therapy. The association of high NT-proBNP and high PRA identified a subgroup (22% of the study population) with the greatest risk of cardiac death. In conclusion, PRA resulted an independent prognostic marker in patients with systolic heart failure additive to NT-proBNP level and ejection fraction. PRA might help to select those patients needing an enhanced therapeutic effort, possibly targeting incomplete renin-angiotensin-aldosterone system blockade.

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.

Comparison of brain natriuretic peptide (BNP) and amino-terminal ProBNP for early diagnosis of heart failure.

BACKGROUND: We compared the diagnostic accuracy of brain natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) for diagnosis of preclinical and mild heart failure (HF). METHODS: We assayed plasma NT-proBNP and BNP in 182 healthy controls and in a prospective cohort of 820 HF patients divided according to the American Heart Association/American College of Cardiology classification. These included 86 patients in stage A [mean (SE) ejection fraction 61% (1%); mean (SE) age 47 (2) years], 255 in stage B [65% (2%); 62 (1) years], 420 patients in stage C [35% (1%); 68 (1) years] and 59 in stage D [25% (1%); 74 (1) years]. Diagnostic accuracies of BNP and NT-proBNP were evaluated by ROC analysis, and a multivariate linear regression model was applied to predict HF staging. RESULTS: Median BNP and NT-proBNP concentrations increased from stage A to D 57-fold and 107-fold, respectively. Both assays were accurate (P <0.001) in separating stage B from controls or stage A, and stage C from controls or stage A or B. NT-proBNP was more accurate (P <0.001) than BNP in differentiating stage C from stages A and B patients and controls and was a better predictor of HF classification in a model including age, sex, and renal function (P <0.001). CONCLUSIONS: Monitoring BNP or NT-proBNP enabled identification of asymptomatic patients at risk for the development of HF. NT-proBNP showed better accuracy than BNP for identifying mild HF.

Aerobic training decreases B-type natriuretic peptide expression and adrenergic activation in patients with heart failure.

OBJECTIVES: We sought to evaluate the effect of physical training on neurohormonal activation in patients with heart failure (HF). BACKGROUND: Patients with HF benefit from physical training. Chronic neurohormonal activation has detrimental effects on ventricular remodeling and prognosis of patients with HF. METHODS: A total of 95 patients with HF were assigned randomly into two groups: 47 patients (group T) underwent a nine-month training program at 60% of the maximal oxygen uptake (VO2), whereas 48 patients did not (group C). The exercise load was adjusted during follow-up to achieve a progressive training effect. Plasma assay of B-type natriuretic peptide (BNP), amino-terminal pro-brain natriuretic peptide (NT-proBNP), norepinephrine, plasma renin activity, and aldosterone; quality-of-life questionnaire; echocardiogram; and cardiopulmonary stress test were performed upon enrollment and at the third and ninth month. RESULTS: A total of 85 patients completed the protocol (44 in group T, left ventricular ejection fraction [EF] 35 +/- 2%, mean +/- SEM; and 41 in group C, EF 32 +/- 2%, p = NS). At the ninth month, patients who underwent training showed an improvement in workload (+14%, p < 0.001), peak VO2 (+13%, p < 0.001), systolic function (EF +9%, p < 0.01), and quality of life. We noted that BNP, NT-proBNP, and norepinephrine values decreased after training (-34%, p < 0.01; -32%, p < 0.05; -26%, p < 0.01, respectively). Increase in peak VO2 with training correlated significantly with the decrease in both BNP/NT-proBNP level (p < 0.001 and p < 0.01, respectively). Patients who did not undergo training showed no changes. CONCLUSIONS: Clinical benefits after physical training in patients with HF are associated with blunting of adrenergic overactivity and of natriuretic peptide overexpression.