The Fondazione Toscana Gabriele Monasterio app: a digital health system to improve wellbeing of inpatients with heart or lung disease.

BACKGROUND: An app providing material for education and entertaining is a possible way to support patients and healthcare providers in achieving person-centered care. METHODS: An app tailored on the Fondazione Toscana Gabriele Monasterio (FTGM), a research hospital treating cardiac and lung disorders, was created. A pilot evaluation project was conducted on consecutive patients hospitalized for heart or lung disorders. Patients were asked to complete an assessment questionnaire. RESULTS: The FTGM app provides information on diagnostic and therapeutic investigations, hospital and healthcare personnel, and includes content for entertainment and learning. It was tested on 215 consecutive patients (75% men, 66% aged >60 years, and 40% with a primary or middle school degree). Sixty-nine percentage of patients used the FTGM app, including 67% of patients aged >80 years and 65% of those with an elementary education (65%). Patients gave positive feedback on the app layout. Many (76%) looked for information on doctors and nurses in the 'People' section. Sixty-five percent of responders had used at least one of the sections called 'Music' and 'Museum visits'. The app helped many patients perceive the hospital as a more liveable place (68%), and to feel less anxious (76%), and more engaged in the diagnostic and therapeutic workup (65%). Overall, the majority of responders (87%) rated the app as 'excellent' or 'good', and almost all (95%) would have recommended other patients to use the app. CONCLUSIONS: The FTGM app is a possible tool to improve patient wellbeing during hospitalization.

[Central apneas and cardiovascular diseases]. / Apnee centrali e malattie cardiovascolari.

Central apneas (CA) and periodic breathing (PB) are the most common related breathing disorders in heart failure, being observed in up to 50% of patients. Once considered only a sleep-related phenomenon, actually CA/PB occur across the whole 24 h period and their presence in the awake patient even in the upright position and during physical effort has been associated with a worse clinical profile and a greater mortality. Chemoreflex activation, circulatory time delay and altered plant gain are the pathophysiological determinants. While the use of guideline-recommended medical and device treatment represents the first step in the management of CA in heart failure patients, no specific therapy has been demonstrated to reduce CA-related impact on mortality. In particular, the use of non-invasive ventilation has yielded contradictory results in the context of large-scale randomized clinical trials. The design and testing of therapies targeting the pathophysiological triggers of CA, such as chemoreflex sensitivity, may prove valuable in the next future.

Biopsy Evidence of Sequential Transthyretin and Immunoglobulin Light-Chain Cardiac Amyloidosis in the Same Patient.

Currently adopted diagnostic flow charts consider transthyretin and light-chain cardiac amyloidosis as mutually exclusive. Here, we report for the first time, to our knowledge, the demonstration of a biopsy-proven dual pathology in an 80-year-old man with sequential development of both wild-type transthyretin amyloidosis and light-chain cardiac amyloidosis cardiomyopathy over a 3-year timespan. (Level of Difficulty: Intermediate.).

Upright Cheyne-Stokes Respiration in Patients With Heart Failure.

BACKGROUND: Cheyne-Stokes respiration (CSR) is believed to only occur in supine and sleeping conditions, and thus, CSR treatment is applied to those specific states. Although CSR has also been described in patients with heart failure (HF) during wakefulness, its persistence in an upright position is still unknown. OBJECTIVES: The purpose of this study was to assess the predictors, clinical correlates, and prognostic value of diurnal CSR in upright position. METHODS: Outpatients with systolic HF underwent a comprehensive evaluation, including short-term respiratory monitoring with a head-up tilt test to investigate the presence of upright CSR, assessment of chemoreflex response to hypoxia and hypercapnia, and 24-h cardiorespiratory recording. At follow-up, cardiac death was considered as the endpoint. RESULTS: Of 574 consecutive patients (left ventricular ejection fraction 32 ± 9%; age 65 ± 13 years; 80% men), 195 (34%) presented supine CSR only, 82 (14%) presented supine and upright CSR, and 297 patients (52%) had normal breathing. Patients with upright CSR had the greatest apnea-hypopnea and central apnea index (at daytime and nighttime), the worst hemodynamic profile and exercise performance, increased plasma norepinephrine and N-terminal pro-B-type natriuretic peptide, and chemosensitivity to hypercapnia, which was the only independent predictor of upright CSR (odds ratio: 3.96; 95% confidence interval [CI]: 1.45 to 10.76; p = 0.007 vs. normal breathing; odds ratio: 4.01; 95% CI: 1.54 to 10.46; p = 0.004 vs. supine CSR). At 8-year follow-up, patients with upright CSR had the worst outcome (log-rank = 14.05; p = 0.001) and the presence of upright CSR independently predicted 8-year cardiac death (hazard ratio: 2.39; 95% CI: 1.08 to 5.29; p = 0.032). CONCLUSIONS: Upright CSR in HF patients is predicted by increased chemosensitivity to hypercapnia and is associated with worse clinical conditions and with a greater risk of cardiac death.

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.

Effect of Sex on Reverse Remodeling in Chronic Systolic Heart Failure.

OBJECTIVES: This study sought to investigate sex-related differences in reverse remodeling (RR). BACKGROUND: RR, that is, the recovery from left ventricular (LV) dilation and dysfunction in response to treatment for heart failure (HF), is associated with improved prognosis. METHODS: Data from patients with stable systolic HF (LV ejection fraction [LVEF] of <50%) undergoing 2 transthoracic echocardiograms within 12 ± 2 months were analyzed. Reverse remodeling was defined as a ≥15% reduction in LV end-systolic volume index. RESULTS: A total of 927 patients were evaluated (68 ± 12 years; median LVEF = 35% [interquartile range: 30% to 43%]; 27% women). Ischemic HF was less often encountered in women (33% vs. 60%, respectively; p < 0.001), whereas most characteristics did not differ with regard to sex. Women showed a higher incidence of RR (41% vs. 27%, respectively; p < 0.001), despite similar baseline LV volume and function. RR was more frequent among women in the subgroups with either ischemic or nonischemic HF, as well as in all categories of systolic dysfunction (LVEF ≤35% or >35%, according to current indication for device implantation, and LVEF <40% or 40% to 50% according to the definition of HF with reduced or mid-range EF). In the whole population, female sex was an independent predictor of RR (hazard ratio: 1.54; 95% confidence interval: 1.11 to 2.14; p = 0.011), together with cause of HF, disease duration, and left bundle branch block. Female sex was again an independent predictor of RR in all LVEF categories. CONCLUSIONS: Reverse remodeling is more frequent among women, regardless of cause and severity of LV dysfunction. Female sex is an independent predictor of RR in all categories of LV systolic dysfunction.

Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure.

BACKGROUND: Large trials using noninvasive mechanical ventilation to treat central apnea (CA) occurring at night ("sleep apnea") in patients with systolic heart failure (HF) have failed to improve prognosis. The prevalence and prognostic value of CA during daytime and over an entire 24-h period are not well described. OBJECTIVES: This study evaluated the occurrence and prognostic significance of nighttime, daytime, and 24-h CA episodes in a large cohort of patients with systolic HF. METHODS: Consecutive patients receiving guideline-recommended treatment for HF (n = 525; left ventricular ejection fraction [LVEF] of 33 ± 9%; 66 ± 12 years of age; 77% males) underwent prospective evaluation, including 24-h respiratory recording, and were followed-up using cardiac mortality as an endpoint. RESULTS: The 24-h prevalence of predominant CAs (apnea/hypopnea index [AHI] ≥5 events/h, with CA of >50%) was 64.8% (nighttime: 69.1%; daytime: 57.0%), whereas the prevalence of predominant obstructive apneas (OA) was 12.8% (AHI ≥5 events/h with OAs >50%; nighttime: 14.7%; daytime: 5.9%). Episodes of CA were associated with neurohormonal activation, ventricular arrhythmic burden, and systolic/diastolic dysfunction (all p < 0.05). During a median 34-month follow-up (interquartile range [IQR]: 17 to 36 months), 50 cardiac deaths occurred. Nighttime, daytime, and 24-h moderate-to-severe CAs were associated with increased cardiac mortality (AHI of 

The search for efficient diagnostic and prognostic biomarkers of heart failure.

Several biomarkers have been tested for screening, diagnosis and prognosis purposes, as well as to guide treatment in heart failure, but only the assay of circulating B-type natriuretic peptides has widely recognized applications for clinical decision-making. Natriuretic peptides are sensitive in detecting the clinically overt or subclinical myocardial damage, but their plasma levels are increased following every generic insult to the cardiovascular system. Novel biomarkers are required to identify specific pathways of disease progression, such as diverse neurohormonal axes activation, inflammation and fibrogenesis, and to act as a tool for therapeutic tailoring. In this view, Gal-3 and ST-2 assays seem very promising, given their involvement in mechanisms of cardiac fibrosis and their prognostic value.

Usefulness of High-Sensitive Troponin Elevation After Effort Stress to Unveil Vulnerable Myocardium in Patients With Heart Failure.

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.

Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?

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.

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.

Prognostic value of alveolar volume in systolic heart failure: a prospective observational study.

BACKGROUND: Ventilatory impairment is known to occur in patients with heart failure (HF). Alveolar volume (VA) is measured by the dilution of an inert gas during a single breath-hold maneuver. Such measurement is sensitive to ventilatory disturbances. We conducted a prospective, observational study to establish the prognostic value of VA in systolic HF. METHODS: We studied 260 consecutive patients who were hospitalized for systolic HF. All patients were evaluated under stable clinical conditions, before hospital discharge. Lung function studies included spirometry and determination of the lung diffusing capacity for carbon monoxide (DLCO) by the single-breath method. We also measured the cardiothoracic ratio on frontal chest radiographs, and the circulating levels of N-terminal pro-hormone of B-type natriuretic peptide (NT-proBNP). The hazard ratio (HR) of death was estimated with Cox regression, and the percentiles of survival time with Laplace regression. For survival analysis, VA was categorized as < 80% (n = 135), or ≥ 80% of the predicted value (n = 125). RESULTS: Follow-up had a median duration of 2.7 years (interquartile range, 1.1 to 4.2 years). The crude mortality rate was 27% in the whole sample, 36% in patients with VA < 80%, and 16% in those with VA ≥ 80%. The HR of death was 2.3-fold higher in patients with VA < 80% than in those with VA ≥80% (p = 0.002). After adjusting for age, New York Heart Association class III-IV, cardiothoracic ratio >0.5, NT-proBNP, persistent atrial fibrillation, DLCO, COPD comorbidity, use of beta-blockers and angiotensin converting enzyme inhibitors, the HR decreased to 1.9 but remained statistically significant (p = 0.039). Two percent of the patients with VA < 80% died about 0.9 years earlier than those with VA ≥ 80% (p = 0.033). The difference in survival time at the 20th percentile was 0.8 years. CONCLUSIONS: VA is a significant, independent predictor of reduced survival in patients with systolic HF.

Prognostic value of plasma renin activity in heart failure patients with chronic kidney disease.

BACKGROUND: Impairment of kidney function is frequently observed in chronic heart failure (CHF). It correlates with clinical and neurohormonal status, and affects prognosis. We aimed to identify the prognostic impact of plasma renin activity (PRA) in patients affected by CHF with chronic kidney disease (CKD). METHODS: We enrolled 996 consecutive CHF patients (age 65 ± 13 years, mean ± SD, left ventricular ejection fraction, LVEF, 33 ± 10%), who underwent a complete clinical and neurohormonal characterization and were then followed-up (median 36 months) for the end point of cardiac death. RESULTS: A stage ≥ 3 CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) was found in 437 patients. Impaired renal function was associated with worse symptoms, lower LVEF, higher plasma norepinephrine, NT-proBNP and PRA (all p<0.001). As compared to patients with preserved renal function, those with CKD had higher cardiac mortality [106 (24%) vs 53 (9.5%), p<0.001]. In CKD patients, at Cox multivariate analysis, only ejection fraction (HR 0.91, 95% CI 0.84-0.97, p=0.008), NT-proBNP (2.53, 1.45-4.41, p=0.001) and PRA (1.73, 1.16-2.58, p=0.007) were independent predictors of cardiac death. ROC analysis identified a cut-off value for PRA of 3.29 ng/mL/h that predicted prognosis with the greatest accuracy. Finally, the elevation of both NT-proBNP and PRA identified a subset of patients with the highest risk of cardiac death. CONCLUSIONS: PRA has an independent prognostic value in CHF patients with CKD comorbidity. The combination of PRA and NT-proBNP identifies a group of high risk patients, who might benefit of a more intensive care, targeted to enhance renin-angiotensin system antagonism.

Daptomycin concentrations in valve tissue and vegetation in patients with bacterial endocarditis.

In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 µg/g, respectively, and 26 µg/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 µg/g in the valve and 18.1 µg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase.

Low triiodothyronine and exercise capacity in heart failure.

BACKGROUND: Cardiopulmonary exercise test (CPT) has a prominent value in assessing clinical severity in chronic heart failure (HF) patients. Reduced free triiodothyronine (fT3) plasma level is associated with a more severe disease and prognosis. The aim of this study was to evaluate the relationship between low fT3 plasma level and reduced exercise capacity in chronic HF, and to determine the influence of a low T3 status in subsets of patients with different functional impairment. METHODS AND RESULTS: 240 HF patients (79% males; age 62 ± 12 years, mean ± standard deviation; left ventricular ejection fraction, EF, 30 ± 9%) underwent a CPT, clinical and neurohormonal characterization (assay for plasma brain natriuretic peptide, BNP, norepinephrine, aldosterone, renin activity, fT3, free T4, thyroid-stimulating hormone). At multivariate analysis in the whole population, age, gender and BNP level were independently associated with peak VO2, whereas in patients with severe functional impairment (peak VO2 < 14 ml/min/kg) fT3 resulted independently related to peak VO2, together with gender and BNP. When patients with peak VO2 < 14 ml/min/kg were divided according to fT3 levels, patients with low T3 syndrome showed reduced exercise capacity and worse ventilatory efficiency. CONCLUSIONS: BNP and fT3 are independently associated with exercise capacity in severely compromised HF patients.

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.