CLINICAL STUDY: HEART FAILURE
Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure
Mark T. Kearney, DM*,*,
Keith A. A. Fox, FRCP ,
Amanda J. Lee, MSc ,
Robin J. Prescott, PhD,
Ajay M. Shah, FRCP*,
Philip D. Batin, DM||,
Wazir Baig, MD¶,
Stephen Lindsay, MD#,
Timothy S. Callahan, PhD**,
William E. Shell, MD,
Dwain L. Eckberg, MD,
Azfar G. Zaman, MD ,
Simon Williams, MRCP||||,
James M. M. Neilson, PhD and
James Nolan, MD¶¶
* King’s College, London, United Kingdom
Department of Cardiology, Edinburgh, United Kingdom
Medical Statistics Unit, Edinburgh, United Kingdom
Department of Medical Physics, University of Edinburgh, Edinburgh, United Kingdom
|| Pontefract and Wakefield Hospitals, Pontefract and Wakefield, United Kingdom
¶ Doncaster Royal Infirmary, Doncaster, United Kingdom
# Bradford Royal Infirmary, Bradford, United Kingdom
** Phase5 Sciences, Los Angeles, California, USA
NETT Foundation, Los Angeles, California, USA
Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia, USA
Freeman Hospital, Newcastle, United Kingdom
|||| Arrow Park Hospital, Liverpool, United Kingdom
¶¶ North Staffordshire Cardiac Centre, Stoke-on-Trent, United Kingdom
Manuscript received February 25, 2002;
revised manuscript received May 31, 2002,
accepted July 24, 2002.
* Reprint requests and correspondence: Dr. Mark T. Kearney, Department of Cardiology, GKT School of Medicine, Kings College London, Bessemer Road, Denmark Hill, London SE5 9PJ, UK.
mark.kearney{at}kcl.ac.uk
 |
Abstract
|
|---|
OBJECTIVES: The aim of this study was to explore the value of noninvasive predictors of death/mode of death in ambulant outpatients with chronic heart failure (HF).
BACKGROUND: Mortality in chronic HF remains high, with a significant number of patients dying of progressive disease. Identification of these patients is important.
METHODS: We recruited 553 ambulant outpatients age 63 ± 10 years with symptoms of chronic HF (New York Heart Association functional class, 2.3 ± 0.5) and objective evidence of left ventricular dysfunction (ejection fraction <45%, cardiothoracic ratio >0.55, or pulmonary edema on chest radiograph). After 2,365 patient-years of follow-up, 201 patients had died, with 76 events due to progressive HF.
RESULTS: Independent predictors of all-cause mortality assessed with the Cox proportional hazards model were as follows: a low standard deviation of all normal-to-normal RR intervals (SDNN); lower serum sodium and higher creatinine levels; higher cardiothoracic ratio; nonsustained ventricular tachycardia; higher left ventricular end-systolic diameter; left ventricular hypertrophy; and increasing age. Independent predictors of death specific to progressive HF were SDNN, serum sodium and creatinine levels. The hazard ratio of progressive HF death for a 10% decrease in SDNN was 1.06 (95% confidence interval [CI], 1.01 to 1.12); for a 2 mmol/l decrease in serum sodium, 1.22 (95% CI, 1.08 to 1.38); and for a 10 µmol/l increase in serum creatinine, 1.14 (95% CI, 1.09 to 1.19) (all p < 0.01).
CONCLUSIONS: In ambulant outpatients with chronic HF, low serum sodium and SDNN and high serum creatinine identify patients at increased risk of death due to progressive HF.
|
Abbreviations and Acronyms
| | ACE | | angiotensin-converting enzyme | | CI | | confidence interval | | EF | | ejection fraction | | eGFR | | estimated glomerular filtration rate | | HF | | heart failure | | HFP | | high-frequency power | | HR | | hazards ratio | | HRV | | heart rate variability | | LFP | | low-frequency power | | NYHA | | New York Heart Association | | ROC | | receiver operating characteristic | | SDNN | | standard deviation of all normal-to-normal RR intervals | | TP | | total power | | UK-HEART | | United Kingdom Heart failure Evaluation and Assessment of Risk Trial | | VLFP | | very low-frequency power |
|
Over a half million new cases of chronic heart failure (HF) are diagnosed each year in the U.S. (1). Despite advances in understanding of the pathophysiology of chronic HF and improvements in its therapy, mortality in ambulant outpatients with controlled symptoms currently remains  10% per year (2,3). A substantial proportion of these deaths are due to a progressive decline in left ventricular function (2,3). It is not fully understood why some patients who have a period of compensated HF after an initial cardiac insult subsequently enter into an irreversible process of declining ventricular function. There is compelling evidence, however, that autonomic and neurohumoral mechanisms play a critical role in mediating this decline in cardiac function (4). Agents such as beta-blockers and angiotensin-converting enzyme (ACE) inhibitors that inhibit specific neurohumoral mechanisms prolong life in chronic HF patients, at least in part, by slowing disease progression (2,5,6). Variables that reflect the magnitude of neurohumoral dysfunction, therefore, may help to identify patients with chronic HF who are at increased risk of entering a decompensated spiral of declining ventricular function, hemodynamic deterioration, and death due to progressive HF.
Several studies have reported variables that might identify patients with chronic HF who are at high risk of death, and their modes of death (7–10). Most of these studies are retrospective analyses of data from trials of therapeutic agents, where risk stratification was not the primary objective (7–9). Additionally, some of these studies were conducted in patients with severe HF (8,9) who may be easier to identify with bedside assessment, and who have annual mortality rates >30% (11).
Treatments aimed at preventing death from progressive HF, as opposed to sudden death, may and currently do require different strategies. Therefore, identifying patients at risk of death specifically from progressive HF may help to tailor further investigation or therapy. The United Kingdom Heart failure Evaluation and Assessment of Risk Trial (UK-HEART) was prospectively designed to assess the value of noninvasive predictors of mortality and mode of death (including noninvasive measurements of neurohumoral function) in ambulant outpatients with chronic HF. We now report on five-year follow-up of our study cohort, with the principal focus of this report on variables that specifically identify patients at increased risk of death due to progressive HF. The current study has the longest follow-up of its type and adds to previous work by evaluating the long-term prognostic utility of both time- and frequency-domain measurements of heart rate variability (HRV).
|
Methods
|
|---|
Patient enrollment.
The UK-HEART was a prospective study carried out in cardiology outpatient clinics of eight United Kingdom general hospitals, between December 1993 and April 1995 (12). Consecutive patients of either gender, age 18 to 85 years, with chronic HF were recruited on the basis of predefined inclusion and exclusion criteria. The ethical committee at each institution approved the protocol, and all patients gave informed consent. Patients were eligible for the trial if they were ambulant outpatients with stable clinical signs and symptoms of chronic HF present for at least three months. We required that symptoms be associated with objective evidence of cardiac dysfunction at rest (pulmonary venous congestion, pulmonary edema, a cardiothoracic ratio >0.55 on at least one chest radiograph, or a radionuclide or echocardiographic ejection fraction [EF] <45%). To avoid possible confounding effects on measurements of neurohumoral activity, patients were excluded if they had a condition associated with impaired autonomic function (diabetes mellitus or chronic renal failure unrelated to HF), a history of alcohol abuse, autonomic neuropathy, or a recent (<3 months) myocardial infarction. Patients with documented constrictive or hypertrophic cardiomyopathy, sustained nonsinus dysrhythmias, atrioventricular conduction defects, or a comorbid noncardiac disease likely to limit survival were also excluded.
Baseline data collection
At the time of recruitment, a case record form detailing baseline clinical and demographic data was completed for each patient. An erect posteroanterior chest radiograph was obtained, and the cardiothoracic ratio was measured. A venous blood sample was taken at rest for measurements of electrolyte concentrations and assessment of renal and liver function. Two-dimensional and M-mode echocardiography were performed according to American Society of Echocardiography recommendations. Left ventricular cavity dimensions, EF, and fractional shortening index were calculated according to standard formulas. All patients were registered with the United Kingdom Office of Population Censuses and Surveys, which notified the Steering Committee of all deaths.
Ambulatory and 12-lead electrocardiography
Twenty-four hour ambulatory electrocardiogram recordings (Tracker, Reynolds Medical, UK) were obtained in all patients during normal, unrestricted out-of-hospital activity. Recordings were analyzed with a Reynolds Medical Pathfinder system by independent technical staff blinded to patient characteristics and outcome data. Nonsustained ventricular tachycardia was defined as three or more consecutive ventricular ectopic beats at a rate >120 beats/min. Left ventricular hypertrophy was assessed using the Sokolow-Lyon voltage (sum of the amplitude of the S-wave on lead V1 and the R-wave on V5 or V6  3.5 mV).
Time-domain analyses of HRV
After initial arrhythmia analysis and editing, normal-to-normal RR intervals were identified, and HRV in the time-domain was measured, according to published guidelines (13). Standard deviation of all normal-to-normal RR intervals (SDNN) is an index of total HRV. We have previously demonstrated that SDNN is a better prognostic marker than other time-domain measurements and, therefore, confined our prognostic studies to this index (12).
24-h frequency-domain HRV analyses
Frequency-domain analyses were made for the first 5 min of each hour and averaged. Fast Fourier transform power spectra (with linear interpolation over missing data, resampling at 0.5 Hz, and Hamming windowing) were integrated over all frequencies total power (TP): 0.0033 to 0.04 Hz very low-frequency power (VLFP); 0.04 to 0.15 Hz low-frequency power (LFP); and 0.15 to 0.40 Hz high-frequency power (HFP) (14,15).
Classification of cause of death
Classification criteria for the cause of death were defined before the study commenced. All deaths reported to the Steering Committee were evaluated by at least two senior physicians, who reviewed death certificates, autopsy findings, and hospital and general practitioners’ records. Where these physicians did not agree on the cause of death, the case was adjudicated by the lead investigator. The mode of death was classified as: 1) sudden cardiac, if it occurred within 1 h of a change in symptoms or during sleep, or while the patient was unobserved; 2) progressive HF, if death occurred after a documented period of symptomatic or hemodynamic deterioration; 3) other cardiovascular death, if death did not occur suddenly and was not associated with progression of HF; and 4) noncardiovascular death.
Statistical analysis
Descriptive group data are given as mean ± SD unless stated otherwise. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease method (16). Natural logarithms were used for all HRV measurements and cardiothoracic ratios. The Cox proportional hazards regression model was used to determine which measurements were related significantly to mortality during the follow-up period, using a multivariate forward and backward stepping model. The Cox model has advantages over other techniques such as logistic regression. It takes into consideration variable duration of follow-up, censoring of subjects, proportionality of event occurrence, and time to event. For the prediction of progressive HF, observations were censored if the patient died of another cause of death; these patients were included in the analysis only up to the time that they died. The causes of death may not be entirely independent, and this could have an effect on the model. We used receiver operating characteristic (ROC) analysis to generate C-statistics. The ROC curves plot the positive fraction, or sensitivity against the false positive fraction (1-specificity) by varying the threshold value for the test. The ROC curve indicates the probability of a true positive result as a function of the probability of a false positive result for all possible threshold values. A C-statistic of 0.5 indicates that the test results are no better than those obtained by chance, whereas an area of 1.0 indicates a perfectly sensitive and specific test.
For the prediction of progressive HF, variables entered into the model were age, gender, the presence or absence of nonsustained ventricular tachycardia, ventricular hypertrophy, left ventricular end-systolic/diastolic diameters, EF, sodium, potassium, urea, creatinine, and the natural logarithms of the cardiothoracic ratio, SDNN, VLFP, LFP, HFP, and TP. Where appropriate, Kaplan-Meier cumulative mortality curves were plotted to display trends in mortality over time and risk ratio. A value of p < 0.05 was taken as statistically significant. The present study has more events and longer follow-up than our previous report and most other studies in this area and, thus, higher statistical power.
|
Results
|
|---|
Patient characteristics.
A total of 553 white patients were recruited in cardiology outpatient clinics. Patients’ mean age (and range) was 62.7 ± 9.7 years (18 to 85 years); 76% were male; 2% were categorized as New York Heart Association (NYHA) functional class I, 59% as class II, and 39% as class III. The average NYHA functional class was 2.3 ± 0.5. Mean serum creatinine was 121 ± 40.8 µmol/l (60 to 340 µmol/l), and mean sodium was 140 ± 3.2 mmol/l (122 to 148 mmol/l). Of the patients, 76% had ischemic heart disease as the etiology of their HF, 38% had nonsustained ventricular tachycardia, and 10% had left ventricular hypertrophy.
Most patients (82%) were treated with ACE inhibitors (mean enalapril dose: 12 ± 0.3 mg/day) and loop diuretics (99%, mean furosemide dose: 71 ± 69 mg/day). Of the patients, 19% were taking digoxin at a mean dose of 198.0 ± 7.1 µg/day; 14% of patients were taking amiodarone (all 200 mg/day); and 7.9% took atenolol at a mean dose of 43.7 ± 1.6 mg/day. Information on deaths was recorded up to and including April 2000, allowing five-year survival status to be determined for all patients. Follow-up was complete on all patients. Of the cohort recruited, 433 patients had 24-h Holter recordings suitable for HRV analysis (all had recordings suitable for arrhythmia analysis).
HF severity
The mean left ventricular EF was 42 ± 17% (6% to 88%), left ventricular end-diastolic diameter was 6.2 ± 1.0 cm (3.2 to 9.4 cm), left ventricular end-systolic diameter was 5.0 ± 1.2 cm (1.7 to 9.2 cm), and cardiothoracic ratio was 0.53 ± 0.07 (0.34 to 0.88). The mean SDNN was 114 ± 41 ms (17 to 264 ms).
Mortality
An EF of <45% was only one entrance criterion for the present study (see the Methods section). Of the study population, 64% had EFs  45%, with a total mortality at five years of 42% (with 16% dying of progressive HF and 15% dying suddenly). A total of 202 patients (36%) had EFs >45%, with a total mortality at five years of 28% (10% progressive HF and 8% sudden death). At 5 years (2,365 patient-years), 201 patients had died (mean annual mortality rate: 7.3%); 67 (33%) of sudden death; 76 (38%) of progressive HF; 24 (12%) of other cardiac causes; and 34 (17%) of noncardiac causes (Figs. 1A to 1D) .
Predictors of all-cause mortality
In multivariate analysis, eight variables provided independent prognostic information that identified patients at increased risk of death from any cause (Table 1): SDNN, serum sodium and creatinine, cardiothoracic ratio, nonsustained ventricular tachycardia, left ventricular end-systolic diameter, the presence of electrocardiographic left ventricular hypertrophy, and increased age (Table 1). The C-statistic for the all-cause mortality model is 0.78. When expressing renal function using eGFR it remained an independent predictor of all-cause mortality, hazards ratio (HR) 1.32 (95% confidence interval [CI] 1.13 to 1.53) for every 10 ml/min/1.73 m2 decrement in eGFR (p < 0.001).
Predictors of death due to progressive HF
Seventy-six patients died of progressive HF (Table 1). In multivariate analysis, independent and specific predictors of progressive HF death were SDNN and serum sodium and creatinine (C-statistic: 0.77). When expressing renal function using eGFR, it remained an independent predictor of death due to progressive HF, HR 1.83 (95% CI 1.44 to 2.32) for every 10 ml/min/1.73 m2 decrement in eGFR (p < 0.001).
These predictors remained important irrespective of EF and etiology of chronic HF. The power of serum sodium, creatinine, and SDNN to predict all-cause mortality or progressive HF death did not change over the period of follow-up. Figure 1A shows mode of death in patients with left ventricular EF >45% and <45%. Figures 1B to 1D show Kaplan-Meier curves demonstrating the proportion of patients free of death due to HF, with the population dichotomized by median values of SDNN, sodium, and creatinine.
|
Discussion
|
|---|
Our principal new findings are that measurements of SDNN and serum sodium and creatinine levels can identify patients with relatively mild disease who are at high risk of death specifically due to progressive HF over a five-year period. In our study, 24-h frequency-domain measurements of HRV did not provide additional prognostic information over the simple time-domain measurement SDNN.
HRV and progressive HF.
In an earlier report (12) we showed that SDNN had potential value as an independent and powerful predictor of mortality due to progressive HF during approximately one-year follow-up. The current complete five-year report has substantially greater power and provides novel, clinically important information showing that among the more complex frequency-domain measurements of HRV added to the current analysis, SDNN remained the most important marker of risk for death preceded by progressive HF.
The intriguing observation that SDNN specifically predicts HF progression probably derives from influences of the multiple neurohormonal factors that modulate SDNN, an index of global HRV. In healthy subjects, HRV reflects primarily fluctuations of cardiac autonomic activity. Published evidence makes the linkage between reduction of cardiac autonomic activity, captured in our study by the SDNN measurement, and progression of HF highly plausible. Patients with HF have increased muscle sympathetic nerve activity (17–19), cardiac norepinephrine spillover (an index of sympathetic nerve traffic to the heart (19), plasma catecholamine levels (20), and renin activity (21). Both sympathetic stimulation (22) and angiotensin (23) reduce vagally mediated heart rate fluctuations. (Conversely, increased vagal activity reduces myocardial norepinephrine release.) Reductions of vagally mediated heart rate fluctuations found in patients with HF (24,25) are directly proportional to the level of muscle sympathetic nerve activity and plasma norepinephrine levels (18).
In addition, there is an intimate relationship between the sympathetic and renin-angiotensin-aldosterone systems, such that stimulation of one increases activity in the other (26). Both norepinephrine (27) and angiotensin II (28) are powerful promoters of cardiac myocyte hypertrophy and necrosis, and there is compelling evidence that norepinephrine and angiotensin II play pivotal roles in promoting the progression of clinical HF (4).
Another potential explanation for the ability of SDNN to predict HF progression is that SDNN is a marker for changes of myocardial size and geometry, both of which may be involved with HF progression (29). A recent study shows that chronic sinoatrial node stretch reduces HRV (30), suggesting that SDNN may be a marker for adverse changes of cardiac morphology, a possibility that warrants further study. We have previously demonstrated that ACE inhibitors augment HRV in patients with chronic HF (31). Of the population we studied, over 80% were already stabilized on these agents; despite this, SDNN remained an important predictor of progressive HF death.
Hyponatremia and progressive HF
We have shown, in a prospective study conducted in the ACE inhibitor era, that hyponatremia in ambulant outpatients with chronic HF is a predictor of mortality from pump failure. Lee and Packer (32), in a trial not specifically designed to identify prognostic factors, reported that patients with severe chronic HF (with mean EF 17%) and serum sodium levels <137 mmol/l) have a life expectancy half that of patients with serum sodium levels >137 mmol/l. More recently, Aaronson et al. (33) showed in a group of patients referred for cardiac transplantation (with mean EF 20%) that serum sodium levels are relatively weak predictors of all-cause mortality, in an already high-risk group of patients. The mechanism by which hyponatremia predicts HF progression may involve neurohumoral activity, including particularly that of the renin-angiotensin-aldosterone system. Although not demonstrated in the current cohort of patients, serum sodium correlates closely with plasma renin activity (5). It is notable that in the study of Lee and Packer (32), prognosis improved in those patients whose serum sodium levels increased in response to ACE inhibition.
Serum creatinine and progressive HF
Alterations of fluid and electrolyte homeostasis are important in the pathophysiology of chronic HF (32). Two recent reports highlight the potential value of impaired renal function as a marker for increased risk of death in chronic HF. Hillege et al. (34), in a retrospective analysis of the Second Prospective Randomized study of Ibopamine on Mortality and Efficacy study, showed that creatinine clearance derived from serum creatinine, body weight, and age is the most powerful predictor of all-cause mortality in patients with NYHA functional class III to IV HF symptoms and EFs <30%. The authors of that study did not attempt to determine the mode of death. Consonant with these findings and those of the present report, Dries et al. (35), in a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) database, demonstrated that moderate renal insufficiency is an independent predictor of all-cause mortality and progressive HF. The SOLVD study, however, excluded patients with creatinine >177 µmol/l. The present study shows that across a wide range (60 to 340 µmol/l), each 10 µmol/l increment of creatinine level increases the risk of a progressive HF death by 14%.
While we can only speculate on the pathophysiologic mechanisms underlying the correlation between renal impairment and left ventricular dysfunction, our data do not suggest that renal function is simply a marker for impaired cardiac output. We found no correlation between serum creatinine levels and any index of cardiac mechanical performance. Thus, it appears that renal dysfunction per se may contribute to HF progression. The mechanisms underlying this detrimental cardiorenal interaction warrant further investigation.
Predictors of progressive HF in ambulant outpatients
The majority of previous reports discussing risk stratification in chronic HF have focussed on patients with significant systolic dysfunction (10). The present study is the first to assess patients with chronic HF across a wide range of EFs, as one would expect to see in well-controlled population studies of chronic HF (36). Our data provide a novel approach to identify patients with chronic HF with and without preserved left ventricular systolic function, who are at increased risk of death preceded by decompensated HF.
Study limitations
The UK-HEART study was carried out before publication of the landmark trials documenting the benefit of beta-adrenergic blocking drugs and aldosterone antagonists in patients with chronic HF. However, this in itself may be an advantage of the current dataset, in that it allows identification of patients on baseline therapy who warrant more aggressive use of these and possibly other agents. The present study excluded diabetics and, therefore, we cannot extrapolate from our data to the diabetic population. However, when random blood glucose levels were incorporated into our statistical analysis, the predictors of all-cause mortality and mode of death did not change. This suggests that our results may apply to the diabetic population, a possibility that warrants further study.
Determining the cause of death in HF can be difficult. We dealt with this problem by having two senior physicians assess the cause of death, according to strict, predefined criteria. In support of this approach, our data demonstrate levels of SDNN, sodium, and creatinine that were significantly different in patients dying of progressive HF than in the rest of the cohort. Our population was relatively young for patients with chronic HF; therefore, the results of this exploratory analysis should now be assessed and applied in different HF populations.
Conclusions
We report a five-year follow-up of 553 patients presenting with mild-to-moderate HF, who are representative of those seen in cardiology and internal medicine practices. Our study provides insights into the pathophysiology of progressive HF; simple analysis of 24-h ambulatory electrocardiograms and measurement of serum sodium and creatinine levels identify patients at increased risk for terminal decompensated HF. These results refine risk stratification of HF patients and may thereby identify patients who merit aggressive medical treatment or complex therapeutic regimes.
|
Footnotes
|
|---|
Financial support for this study was by the Chest, Heart, and Stroke Association (Scotland) and the Northern and Yorkshire Research and Development Directorate. Drs. Kearney, Fox, and Shah are supported by the British Heart Foundation.
|
References
|
|---|
1. Ghali JK, Cooper R, Ford E. Trends in hospitalization for heart failure in the United States, 1973–1986: evidence for increasing population prevalence. Arch Intern Med. 1990;150:769–773[Abstract/Free Full Text]
2. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007[CrossRef][Medline]
3. The Captopril-Digoxin Multicentre Research Group. Comparative effects of therapy with captopril and digoxin in mild to moderate heart failure. JAMA. 1988;259:539–544[Abstract/Free Full Text]
4. Mann DL. Mechanisms and models in heart failure: a combinatorial approach. Circulation. 1999;100:999–1008[Free Full Text]
5. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13[CrossRef][Medline]
6. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1992;327:685–691[Abstract]
7. Gradman A, Deedwania P, Cody R, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol. 1989;14:564–570[Abstract]
8. Singh SN, Fisher SG, Carson PE, et al. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. J Am Coll Cardiol. 1998;32:942–947[Abstract/Free Full Text]
9. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. Circulation. 2000;101:40–46[Abstract/Free Full Text]
10. Eichorn EJ. Prognosis determination in heart failure. Am J Med. 2001;110:14S–36S[CrossRef][Medline]
11. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717[Abstract/Free Full Text]
12. Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure. Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart). Circulation. 1998;98:1510–1516[Abstract/Free Full Text]
13. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–1065[Free Full Text]
14. Saul JP, Arai Y, Berger RD, et al. Assessment of autonomic regulation in chronic congestive heart failure by spectral heart rate analysis. Am J Cardiol. 1988;61:1292–1299[CrossRef][Medline]
15. Pomeranz B, Macaulay RJB, Caudill MA, et al. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol. 1985;248:H151–153[Medline]
16. Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39:920–929[CrossRef][Medline]
17. Leimbach WN Jr., Wallin BG, Victor RG, et al. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986;73:913–919[Abstract/Free Full Text]
18. Porter TR, Eckberg DL, Fritsch JM, et al. Autonomic pathophysiology in heart failure patients: sympathetic-cholinergic interrelations. J Clin Invest. 1990;85:1362–1371[Medline]
19. Rundqvist B, Elam M, Bergmann-Sverrisdottir Y, et al. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation. 1997;95:169–175[Abstract/Free Full Text]
20. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819–823[Abstract]
21. Dzau VJ, Colucci WS, Hollenberg NK, et al. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981;20:S203–309
22. Taylor JA, Myers CW, Halliwill JR, et al. Sympathetic restraint of respiratory sinus arrhythmia: implications for assessment of vagal-cardiac tone in humans. Am J Physiol. 2001;280:H2804–2814
23. Taylor JA, Carr DL, Myers CW, et al. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation. 1998;98:547–555[Abstract/Free Full Text]
24. Nolan J, Flapan AD, Capewell S, Macdonald T, Neilson JMM, Ewing DJ. Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function. Br Heart J. 1992;27:642–649
25. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med. 1971;285:877–883[Medline]
26. Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262:E763–778[Medline]
27. Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med. 1984;311:850–851[Medline]
28. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res. 1991;69:1185–1195[Abstract/Free Full Text]
29. an International Forum on Cardiac RemodellingCohn JN, Ferrari R, Sharpe N. Cardiac remodelling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodelling. J Am Coll Cardiol. 2000;35:569–582[Abstract/Free Full Text]
30. Horner SM, Murphy CF, Coen B, et al. Contribution to heart rate variability by mechanoelectrical feedback. Stretch of the sinus node reduces heart rate variability. Circulation. 1996;94:1726–1767[Abstract/Free Full Text]
31. Flapan AD, Nolan J, Neilson JMM, et al. Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease. Am J Cardiol. 1992;69:532–535[CrossRef][Medline]
32. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting enzyme inhibition in patients with severe chronic heart failure. Circulation. 1986;73:257–267[Abstract/Free Full Text]
33. Aaronson KD, Schwartz S, Chen T-M, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667[Abstract/Free Full Text]
34. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102:203–210[Abstract/Free Full Text]
35. Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681–689[Abstract/Free Full Text]
36. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol. 1999;33:1948–1955[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
H. Wedel, J. J.V. McMurray, M. Lindberg, J. Wikstrand, J. G.F. Cleland, J. H. Cornel, P. Dunselman, A. Hjalmarson, J. Kjekshus, M. Komajda, et al.
Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): incremental value of apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide
Eur J Heart Fail,
March 1, 2009;
11(3):
281 - 291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Henkel, M. M. Redfield, S. A. Weston, Y. Gerber, and V. L. Roger
Death in Heart Failure: A Community Perspective
Circ Heart Fail,
July 1, 2008;
1(2):
91 - 97.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gheorghiade, W. T. Abraham, N. M. Albert, W. Gattis Stough, B. H. Greenberg, C. M. O'Connor, L. She, C. W. Yancy, J. Young, G. C. Fonarow, et al.
Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry
Eur. Heart J.,
April 2, 2007;
28(8):
980 - 988.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Milo-Cotter, K. F. Adams, C. M. O'Connor, N. Uriel, E. Kaluski, G. M. Felker, B. Weatherley, Z. Vered, and G. Cotter
Acute heart failure associated with high admission blood pressure -- A distinct vascular disorder?
Eur J Heart Fail,
February 1, 2007;
9(2):
178 - 183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Siirila-Waris, J. Lassus, J. Melin, K. Peuhkurinen, M. S. Nieminen, V.-P. Harjola, and for the FINN-AKVA study group
Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure
Eur. Heart J.,
December 2, 2006;
27(24):
3011 - 3017.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K.G. Moore, D. G. Groves, P. E. Barlow, K. A.A. Fox, A. Shah, J. Nolan, and M. T. Kearney
Heart rate turbulence and death due to cardiac decompensation in patients with chronic heart failure
Eur J Heart Fail,
October 1, 2006;
8(6):
585 - 590.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J D Newton and I B Squire
Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure
Heart,
October 1, 2006;
92(10):
1441 - 1446.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. C. Huynh, A. Rovner, and M. W. Rich
Long-term Survival in Elderly Patients Hospitalized for Heart Failure: 14-Year Follow-up From a Prospective Randomized Trial.
Arch Intern Med,
September 25, 2006;
166(17):
1892 - 1898.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Coca, H. M. Krumholz, A. X. Garg, and C. R. Parikh
Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.
JAMA,
September 20, 2006;
296(11):
1377 - 1384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Goldberg, H. Hammerman, S. Petcherski, M. Nassar, A. Zdorovyak, S. Yalonetsky, M. Kapeliovich, Y. Agmon, R. Beyar, W. Markiewicz, et al.
Hyponatremia and Long-term Mortality in Survivors of Acute ST-Elevation Myocardial Infarction.
Arch Intern Med,
April 10, 2006;
166(7):
781 - 786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. W. Yancy, M. Lopatin, L. W. Stevenson, T. De Marco, G. C. Fonarow, and for the ADHERE Scientific Advisory Committee and I
Clinical Presentation, Management, and In-Hospital Outcomes of Patients Admitted With Acute Decompensated Heart Failure With Preserved Systolic Function: A Report From the Acute Decompensated Heart Failure National Registry (ADHERE) Database
J. Am. Coll. Cardiol.,
January 3, 2006;
47(1):
76 - 84.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. A. Khan, I. Ma, C. R. Thompson, K. Humphries, D. N. Salem, M. J. Sarnak, and A. Levin
Kidney Function and Mortality among Patients with Left Ventricular Systolic Dysfunction
J. Am. Soc. Nephrol.,
January 1, 2006;
17(1):
244 - 253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J D Newton, H M Blackledge, and I B Squire
Ethnicity and variation in prognosis for patients newly hospitalised for heart failure: a matched historical cohort study
Heart,
December 1, 2005;
91(12):
1545 - 1550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Vanholder, Z. Massy, A. Argiles, G. Spasovski, F. Verbeke, N. Lameire, and for the European Uremic Toxin Work Group (EUTox)
Chronic kidney disease as cause of cardiovascular morbidity and mortality
Nephrol. Dial. Transplant.,
June 1, 2005;
20(6):
1048 - 1056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Authors/Task Force Members, K. Swedberg, Writing Committee:, J. Cleland, H. Dargie, H. Drexler, F. Follath, M. Komajda, L. Tavazzi, O. A. Smiseth, et al.
Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology
Eur. Heart J.,
June 1, 2005;
26(11):
1115 - 1140.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Edes, Z. Gasior, and K. Wita
Effects of nebivolol on left ventricular function in elderly patients with chronic heart failure: results of the ENECA study
Eur J Heart Fail,
June 1, 2005;
7(4):
631 - 639.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Klein, C. M. O'Connor, J. D. Leimberger, W. Gattis-Stough, I. L. Pina, G. M. Felker, K. F. Adams Jr, R. M. Califf, M. Gheorghiade, and for the OPTIME-CHF Investigators
Lower Serum Sodium Is Associated With Increased Short-Term Mortality in Hospitalized Patients With Worsening Heart Failure: Results From the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Study
Circulation,
May 17, 2005;
111(19):
2454 - 2460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pathak, D. Curnier, J. Fourcade, J. Roncalli, P. K. Stein, P. Hermant, M. Bousquet, P. Massabuau, J.-M. Senard, J.-L. Montastruc, et al.
QT dynamicity: a prognostic factor for sudden cardiac death in chronic heart failure
Eur J Heart Fail,
March 2, 2005;
7(2):
269 - 275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C. Fonarow, K. F. Adams Jr, W. T. Abraham, C. W. Yancy, W. J. Boscardin, and for the ADHERE Scientific Advisory Committee, Stud
Risk Stratification for In-Hospital Mortality in Acutely Decompensated Heart Failure: Classification and Regression Tree Analysis
JAMA,
February 2, 2005;
293(5):
572 - 580.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M P Frenneaux
Autonomic changes in patients with heart failure and in post-myocardial infarction patients
Heart,
November 1, 2004;
90(11):
1248 - 1255.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Ezekowitz, F. A. McAlister, K. H. Humphries, C. M. Norris, M. Tonelli, W. A. Ghali, M. L. Knudtson, and APPROACH Investigators
The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease
J. Am. Coll. Cardiol.,
October 19, 2004;
44(8):
1587 - 1592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Bibbins-Domingo, F. Lin, E. Vittinghoff, E. Barrett-Connor, D. Grady, and M. G. Shlipak
Renal insufficiency as an independent predictor of mortality among women with heart failure
J. Am. Coll. Cardiol.,
October 19, 2004;
44(8):
1593 - 1600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M T Kearney, K A A Fox, A J Lee, W P Brooksby, A M Shah, A Flapan, R J Prescott, R Andrews, P D Batin, D L Eckberg, et al.
Predicting sudden death in patients with mild to moderate chronic heart failure
Heart,
October 1, 2004;
90(10):
1137 - 1143.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. G. Shlipak, G. L. Smith, S. S. Rathore, B. M. Massie, and H. M. Krumholz
Renal Function, Digoxin Therapy, and Heart Failure Outcomes: Evidence from the Digoxin Intervention Group Trial
J. Am. Soc. Nephrol.,
August 1, 2004;
15(8):
2195 - 2203.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. de Groote, J. Dagorn, B. Soudan, N. Lamblin, E. McFadden, and C. Bauters
B-type natriuretic peptide and peak exercise oxygen consumption provide independent information for risk stratification in patients with stable congestive heart failure
J. Am. Coll. Cardiol.,
May 5, 2004;
43(9):
1584 - 1589.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. McAlister, J. Ezekowitz, M. Tonelli, and P. W. Armstrong
Renal Insufficiency and Heart Failure: Prognostic and Therapeutic Implications From a Prospective Cohort Study
Circulation,
March 2, 2004;
109(8):
1004 - 1009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Kearney, J. Nolan, and For the UK-HEART Study Investigators
Uric Acid and Prognosis in Chronic Heart Failure
Circulation,
November 25, 2003;
108
(21):
e148 - e148.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B. Culleton, L. L. Hamm, P. A. McCullough, B. L. Kasiske, E. Kelepouris, M. J. Klag, et al.
Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention
Hypertension,
November 1, 2003;
42(5):
1050 - 1065.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B. Culleton, L. L. Hamm, P. A. McCullough, B. L. Kasiske, E. Kelepouris, M. J. Klag, et al.
Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention
Circulation,
October 28, 2003;
108(17):
2154 - 2169.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Kearney, J. Nolan, A. J. Lee, P. W. Brooksby, R. Prescott, A. M. Shah, A. G. Zaman, D. L. Eckberg, H.S. Lindsay, P. D. Batin, et al.
A prognostic index to predict long-term mortality in patients with mild to moderate chronic heart failure stabilised on angiotensin converting enzyme inhibitors
Eur J Heart Fail,
August 1, 2003;
5(4):
489 - 497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A MacCarthy, M. T Kearney, J. Nolan, A. J Lee, R. J Prescott, A. M Shah, W P. Brooksby, and K. A A Fox
Prognosis in heart failure with preserved left ventricular systolic function: prospective cohort study
BMJ,
July 10, 2003;
327(7406):
78 - 79.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gheorghiade, I. Niazi, J. Ouyang, F. Czerwiec, J.-i. Kambayashi, M. Zampino, and C. Orlandi
Vasopressin V2-Receptor Blockade With Tolvaptan in Patients With Chronic Heart Failure: Results From a Double-Blind, Randomized Trial
Circulation,
June 3, 2003;
107(21):
2690 - 2696.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods
