Methods

From June 2002 to November 2008, we prospectively enrolled 996 consecutive patients with systolic dysfunction (left ventricular ejection fraction [EF] <50%), referred to our division for HF management. The diagnosis of HF was determined by the history, symptoms, physical examination, and instrumental findings for the assessment of structural myocardial involvement. Cardiac morphology and function were assessed by 2-dimensional Doppler echocardiography.

Acute coronary syndrome within 6 months before the enrollment was the only exclusion criterion. The characteristics of the sample population are summarized in Table 1 . All patients were at the maximum tolerated dose of β blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), and aldosterone antagonists and had a controlled dietary sodium daily intake (<4 g NaCl). The study protocol was performed according to the Declaration of Helsinki and was approved by the institutional ethics committee, and all subjects provided informed consent.

All patients underwent a comprehensive biohumoral characterization. Blood samples were drawn at 8.00 a.m. after an overnight fast, according to a standardized experimental protocol. Follow-up started with blood sampling and continued until study termination (i.e., May 2009). Independent interviewers obtained follow-up data directly from the patients, relatives, institute cardiologists, or general practitioners. Information about the time and cause of death was obtained from death certificates, postmortem reports, and family doctors. The primary end point was cardiac death (further distinguished into death from HF progression and sudden death). Appropriate implanted cardioverter defibrillator shocks and sudden death were considered together as a combined end point. Patients who died from noncardiac-related causes or underwent heart transplantation or ventricular assistance device implantation were considered censored at the event.

Statistical analysis was performed using the Statistical Package for Social Sciences, version 13.0 (SPSS, Chicago, Illinois). The data are presented as the mean ± SD or as the median and interquartile range for values with a non-normal distribution. Variables with a skewed distribution were logarithmically transformed for parametric analysis. Continuous variables were compared using Student’s t test, and discrete variables were compared using the chi-square test. The candidate independent variables used on univariate Cox proportional analysis for prognostic aims were selected by their close association with the HF outcome. In particular, we considered age, gender, body mass index, etiology of cardiomyopathy (ischemic/nonischemic), New York Heart Association class, echocardiographic indexes of left ventricular function (EF), hemoglobin, estimated glomerular filtration rate using Cockroft-Gault’s formula, thyroid function (free triiodothyronine), γ-glutammyl-transferase, neurohormones (N-terminal pro-brain natriuretic peptide [NT-proBNP], cortisol, epinephrine, norepinephrine, aldosterone, and PRA), and therapy with diuretics, nitrates, β blockers, ACEIs/ARBs, and spironolactone. All the variables found to be significant on univariate analysis were included in the multivariate Cox proportional hazards model. The optimal cutpoints for PRA and NT-proBNP were quantified using receiver operating characteristic curves. The prognostic value of the spectrum of PRA levels was assessed with the P-spline method, fitting data to a set of spline basis functions with a reduced set of knots, combined with the roughness penalty of smoothing splines. The Kaplan-Meier life table, estimating cardiac-related death, was used to summarize the follow-up experience in the patient population. Differences in survival curves were tested with the log-rank test (Mantel-Cox). The same variables used for the survival analysis were entered into the univariate linear regression analysis to examine the association with PRA, together with the serum glucose, sodium, potassium, thyroid-stimulating hormone, and C-reactive protein. The significant univariate predictors were then entered into the multivariate linear regression analysis. A p value <0.05 was considered significant.

Results

During a median follow-up of 36 months (range 0 to 72), 290 deaths occurred. Of the 290 patients who died, 170 died from cardiac causes (124 from associated HF progression, 26 from sudden death, 15 from acute myocardial infarction, and 5 perioperative), and 27 implanted cardioverter defibrillator shocks were observed. Five patients underwent heart transplantation and one ventricular assist device implantation, as destination therapy.

On Cox univariate analysis age, body mass index, New York Heart Association class, EF, etiology of cardiomyopathy, free triiodothyronine, hemoglobin, estimated glomerular filtration rate, cortisol, γ-glutammyl-transferase, NT-proBNP, PRA, epinephrine, norepinephrine, aldosterone, and therapy with ACEIs/ARBs, spironolactone, nitrates, or diuretics were predictors of cardiac death. On multivariate analysis, only EF, NT-proBNP, and PRA were independent predictors of cardiac death ( Table 2 ).

Table 2

Univariate and multivariate analysis of predictors for cardiac mortality

Variable	Univariate Model		Multivariate Model
	Hazard Ratio (95% CI)	p Value	Hazard Ratio (95% CI)	p Value
Age	1.257 (1.146–1.379)	<0.001	—	—
Body mass index	0.826 (0.751–0.908)	<0.001	—	—
New York Heart Association class	3.855 (2.775–5.356)	<0.001	—	—
Ejection fraction	0.693 (0.634–0.758)	<0.001	0.962 (0.938–0.986)	0.002
Etiology (ischemic)	1.746 (1.278–2.387)	<0.001	—	—
Free triiodothyronine	0.755 (0.671–0.895)	0.001	—	—
Hemoglobin	0.803 (0.740–0.871)	<0.001	—	—
Glomerular filtration rate	0.647 (0.579–0.724)	<0.001	—	—
Cortisol	1.193 (1.134–1.255)	<0.001	—	—
γ-Glutamyltransferase	1.155 (1.073–1.243)	<0.001	—	—
N-terminal pro-brain natriuretic peptide	1.860 (1.682–2.057)	<0.001	1.729 (1.383–2.161)	<0.001
Plasma renin activity	1.293 (1.194–1.401)	<0.001	1.201 (1.024–1.408)	0.024
Epinephrine	1.227 (1.136–1.325)	<0.001	—	—
Norepinephrine	1.308 (1.205–1.419)	<0.001	—	—
Aldosterone	1.127 (1.038–1.223)	0.004	—	—
Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers	0.532 (0.371–0.763)	0.001	—	—
Spironolactone	1.761 (1.249–2.483)	0.001	—	—
Nitrates	1.699 (1.223–2.361)	0.002	—	—
Furosemide	2.352 (1.380–4.008)	0.002	—	—

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