Abstract
Aims
Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to β-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different β-blocker agents and doses.
Methods and results
This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable β-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual β-blocker agents used and the dose equivalent taken, the prevalence of AE was 31–39%. Norepinephrine levels neither correlated with heart rate (r = 0.02; 95% CI: −0.08–0.11; P = 0.74) nor were they related to underlying rhythm (P = 0.09) or the individual β-blocker agent used (P = 0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387–2.645; χ2: 15.60).
Conclusion
We verified the presence of AE in CHF patients on chronic stable β-blocker therapy, irrespective of the individual β-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.
Keywords: Adrenergic escape, β-Blocker, Chronic heart failure, Prognosis
Introduction
Neurohumoral activation represents an important aspect of cardiac physiology in chronic heart failure (CHF). Indicators of activity of the renin–angiotensin–aldosterone system (RAAS) are elevated in CHF. Aldosterone escape—the phenomenon of inadequate medical suppression of RAAS activity despite long-term treatment—has been recognized.1,2 It is verified from elevated hormonal levels during chronic treatment. Furthermore, the relation of aldosterone escape to reduced exercise capacity3 and adverse clinical outcome4 has been demonstrated.
Similar to RAAS, indicators of cardiac adrenergic activity become elevated early in CHF5 and the relation of increased adrenergic activity to adverse clinical outcome has also been recognized.6,7 Adrenergic activity is mainly countered by β-blockers but the effect of individual β-blockers on plasma catecholamine levels remains controversial,8–11 a finding in part attributed to the different properties of individual agents. However, as opposed to previous reports on metoprolol and carvedilol,12,13 it was recently shown14 that β-blockers consistently lower adrenergic activity irrespective of the actual agent chosen.
Given this controversy and in light of the fact that hormonal (aldosterone) escape has already been described for RAAS, it appears conceivable that adrenergic escape might occur with chronic stable β-blocker therapy. As this has not been comprehensively addressed before, we sought to prospectively establish the possible prevalence of adrenergic escape and the resultant prognostic relevance with respect to different β-blocker agents in the setting of a tertiary referral outpatient clinic.
Methods
Patients
In this prospective, observational study, we included a total of 427 patients with chronic stable systolic dysfunction, undergoing evaluation of heart failure at the heart failure outpatient’s department of the University Hospital Heidelberg. Chronic heart failure was established according to published guidelines,15 and was present for more than 1 year in all patients at inclusion. The CHF stability was defined as described subsequently. The choice of medication, most notably the individual β-blocking agent chosen, was at the discretion of the referring physician, and intention to treat was assumed during follow-up. Owing to the frequency of prescription, however, analysis was restricted to metoprolol, carvedilol, and bisoprolol, effectively excluding two patients on celiprolol, eight patients on nebivolol, and two patients on propranolol.
With respect to guideline-recommended CHF medication, patients were on maximum tolerated doses as established by the referring physician. Initiation of treatment had to be performed at least 6 months prior to inclusion and medication had to be stable for at least 1 month prior to inclusion. Exclusion criteria were: a positive history for primary pulmonary disease, uncorrected valvular defects, and cardiac decompenzation requiring inotropic support within the last 3 months prior to study inclusion. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the local Ethics Committee. All patients gave their written informed consent.
In addition, to verify the hypothesis of uncoupling of catecholamine levels and activity by determining their relation to clinical variables, 204 patients with stable systolic dysfunction, who were not receiving β-blocker treatment (mean age 55.3 ± 10.3 years; 77% male), were also recruited.
Blood sampling and testing
Patients were instructed to fast and abstain from caffeinated beverages overnight. Blood samples were taken from a peripheral venous catheter after a resting period of 30 min, immediately centrifuged for 10 min at a relative centrifugation force of 1580 g at 4°C, subdivided, and frozen at −30°C. Testing was performed for plasma norepinephrine and epinephrine levels (high-performance liquid chromatography, Chromosystems GmbH). The upper limit of normal of our local laboratory was 1.625 nmol/L for norepinephrine and 0.464 nmol/L for epinephrine in accordance with the published values.16,17 To convert nmol/L into ng/L, values should be multiplied by 181.82 for epinephrine and 169.49 for norepinephrine (or 0.0055 for epinephrine and 0.0059 for norepinephrine for the inverse conversion). In 246 patients (59%), data on NT-proBNP were available, with equal proportions for both groups [patients in escape: 101 (62%), not in escape: 145 (57%), P = 0.36]. Analysis of NT-proBNP was performed using a fully automated Elecsys® Roche Diagnostics 2010 analyser. Assay precision, analytical sensitivity, interferences, and stability have been described previously.18
Follow-up and endpoints
All patients were followed for a minimum of 12 months. Survival status was established through electronic hospital records, telephone calls to patient’s homes or their physicians. The outcome for the purpose of this analysis was all-cause mortality. No patient underwent implantation of a left-ventricular assist device during follow-up. Patients receiving orthotopic heart transplantation were followed up until their surgical procedure and censored thereafter.
Definition of adrenergic escape and statistics
Referring to the definition of aldosterone escape to ACE-inhibitors1,2 or angiotensin-receptor blockers (ARBs),19 adrenergic escape was defined as a value of the individual hormone (epinephrine, norepinephrine) measured above the upper limit of normal as provided by the local laboratory. We chose this more rigorous definition of escape, rather than using the definition of re-elevation after initial control of hormone levels, as we considered both a situation where β-blockers did not lead to a decrease in catecholamines and a situation where initially β-blockers decreased catecholamines but do not any more, as non-efficacious in the long term.
Contingency tables were used for categorical variables and analysed using χ2 analysis. Differences between continuous variables were assessed using two-sample Wilcoxon test, Kruskal–Wallis test, and ANOVA, and correlation between variables was assessed using Pearson and Spearman methods where appropriate. All tests are two-tailed, and a P-value of <5% was regarded statistically significant. Differences in event-free survival were analysed using Cox proportional hazard models, both uni- and multivariate. The data are presented as mean ± SD, except where specified otherwise. Calculations were performed with SAS, version 6.12.
Results
The median follow-up in surviving patients was 71 (57–94) months. During that time, a total of 120 patients (29%) died, the 1-year mortality being 11% (44 patients). Consequent to the nature of our clinic, patients were relatively young and the majority had dilated cardiomyopathy as the underlying aetiology of CHF. Patients with adrenergic escape were older, had higher NYHA class, a lower ejection fraction (LVEF), and 6 min walk test distance. They more often received spironolactone and loop diuretics. No difference in the prescription of individual β-blocker agents was seen between groups. For complete characteristics see Table 1.
Table 1.
Patient characteristics according to adrenergic escape status as established using norepinephrine cut-off
| All (n = 415) | Below NA cut-off (n = 253) | P | Above NA cut-off (n = 162) | |
|---|---|---|---|---|
| Above ADR cut-off (%) | 19 | 10 | *** | 32 |
| 1 year mortality (%) | 11 | 8 | 0.07 | 14 |
| 3 year mortality (%) | 20 | 16 | * | 27 |
| Gender (% male) | 83 | 84 | 0.69 | 82 |
| Age (years) | 54.5 ± 11.0 | 53.1 ± 11.1 | *** | 56.7 ± 9.5 |
| iCMP (%) | 31 | 27 | 0.07 | 36 |
| NYHA functional class | *** | |||
| I (%) | 13 | 18 | 6 | |
| II (%) | 49 | 52 | 44 | |
| III (%) | 38 | 30 | 50 | |
| BMI (kg/m2) | 26.5 ± 4.6 | 26.9 ± 4.6 | * | 25.9 ± 4.2 |
| iCMP (%) | 31 | 27 | 0.07 | 36 |
| LVEF (%) | 28 ± 11 | 30 ± 11 | *** | 24 ± 9 |
| SR (%) | 68 | 69 | 0.75 | 67 |
| HR (b.p.m.) | 79 ± 17 | 77 ± 17 | 0.09 | 83 ± 41 |
| BPmean (mmHg) | 91 ± 13 | 92 ± 14 | 0.19 | 90 ± 14 |
| 6 min walk test (m) | 469 ± 103 | 492 ± 104 | *** | 434 ± 113 |
| Norepinephrine (nmol/L) | 1.40 (0.96–2.06) | 1.02 (0.71–1.30) | *** | 2.28 (1.88–3.06) |
| Epinephrine (nmol/L) | 0.20 (0.10–0.38) | 0.14 (0.08–0.26) | *** | 0.32 (0.19–0.58) |
| NT-proBNP (pg/mL) | 1574 (592–3261) | 1208 (441–2303) | *** | 2543 (1060–4667) |
| ACE/ARB (%) | 97 | 98 | 0.06 | 94 |
| Metoprolol (%) | 41 | 41 | 0.99 | 41 |
| Carvedilol (%) | 52 | 51 | 0.92 | 52 |
| Bisoprolol (%) | 7 | 8 | 0.85 | 7 |
| BBL dose equivalent (%) | 43.9 ± 30.2 | 46.8 ± 30.1 | ** | 39.3 ± 26.6 |
| Sprionolactone (%) | 37 | 32 | * | 44 |
| Loop diuretic (%) | 71 | 64 | *** | 81 |
NA, norepinephrine; ADR, epinephrine; BMI, body mass index; iCMP, ischaemic cardiomyopathy; LVEF, left ventricular ejection fraction; SR, sinus rhythm; HR, heart rate; BP blood pressure; ACE/ARB, ACE-inhibitor or angiotensin-receptor blocker; BBL, beta-blocker.
*P < 0.05; **P < 0.01; ***P < 0.001.
Plasma hormonal levels and clinical variables
Norepinephrine and epinephrine did not correlate (r = 0.07; 95% CI: −0.02 to 0.17; P = 0.14). Furthermore, neither norepinephrine nor epinephrine correlated with heart rate (r = 0.02; 95% CI: −0.08 to 0.11; P = 0.74 and r = 0.04; 95% CI: −0.06 to 0.13; P = 0.47; respectively). Both norepinephrine and epinephrine only weakly correlated with NT-proBNP (r = 0.41; 95% CI: 0.30–0.51; P < 0.001 and r = 0.24; 95% CI: 0.16–0.35; P < 0.001; respectively). No significant association of plasma levels and underlying rhythm (P = 0.58 for epinephrine and P = 0.09 for norepinephrine) was noted, nor any significant association of plasma levels and individual β-blocker agents (P = 0.97 for epinephrine and P = 0.87 for norepinephrine).
In the non-β-blocker control patients, both norepinephrine and epinephrine correlated with heart rate (r = 0.27; 95% CI: 0.14–0.39; P < 0.001 and r = 0.15; 95% CI: 0.01–0.29; P = 0.03; respectively) as well as NT-proBNP (r = 0.41; 95% CI: 0.29–0.52; P < 0.001 and r = 0.41; 95% CI: 0.29–0.52; P < 0.001; respectively).
Adrenergic escape according to dose equivalent
Though patients with adrenergic escape received a lower mean dose equivalent of β-blocker, plasma levels of norepinephrine did not correlate (r = 0.02; 95% CI: −0.08 to 0.12; P = 0.69) with dose equivalent while plasma levels of epinephrine only weakly correlated (r = −0.11; 95% CI: −0.20 to 0.01; P = 0.03). Overall, 162 patients (39%) showed adrenergic escape as defined by the norepinephrine cut-off. Of these patients, 52 (32%) also had epinephrine levels above the respective cut-off. No difference in the prevalence of adrenergic escape was seen between individual β-blocker agents (metoprolol: 39%; carvedilol: 39%; bisoprolol: 40%; P = 0.99).
When considering only patients with a β-blocker dose equivalent >50% (n = 207), 74 patients (37%) showed adrenergic escape for the norepinephrine cut-off; 21 of these patients (28%) also being positive for the epinephrine cut-off. With a limit of a β-blocker dose equivalent >75% (n = 77), 24 patients (31%) showed adrenergic escape for the norepinephrine cut-off with three of these patients (13%) also being positive for the epinephrine cut-off. Finally, in patients with a β-blocker dose equivalent of 100% (n = 46), 15 patients (33%) showed adrenergic escape for the norepinephrine cut-off with 1 of these patients (7%) also being positive for the epinephrine cut-off. No statistically significant difference in the proportion of patients with adrenergic escape was noted for the different dose equivalent groups as compared with the entire study population (P = 0.69, 0.23, 0.53, respectively).
Prognostic significance of adrenergic escape
Univariate Cox models identified a number of significant indicators of adverse outcome (for complete results, see Table 2). As continuous variables, neither epinephrine nor norepinephrine retained statistical significance. However, adrenergic escape was a strong indicator of mortality using the norepinephrine as well as the epinephrine cut-off. The survival of patients grouped according to adrenergic escape for norepinephrine is shown in Figure 1.
Table 2.
Univariate Cox proportional hazard models for all-cause mortality
| HR | 95% CI | χ2 | P- value | |
|---|---|---|---|---|
| NT-proBNP (100 pg/mL) | 1.013 | 1.008–1.018 | 25.64 | <0.0001 |
| NA_escape | 2.471 | 1.681–3.632 | 21.19 | <0.0001 |
| 6MWT (m) | 0.997 | 0.995–0.998 | 13.24 | <0.0005 |
| ADR_escape | 2.072 | 1.367–3.140 | 11.79 | <0.001 |
| NYHA | 1.506 | 1.131–2.004 | 7.87 | <0.01 |
| LVEF (%) | 0.942 | 0.904–0.983 | 7.62 | <0.01 |
| HR (b.p.m.) | 1.005 | 1.000–1.009 | 4.67 | <0.05 |
| Epinephrine (nmol/L) | 1.100 | 0.950–1.273 | 1.62 | 0.20 |
| Norepinephrine (nmol/L) | 1.006 | 0.981–1.031 | 0.23 | 0.63 |
| Sinus rhythm | 0.949 | 0.686–1.314 | 0.1 | 0.75 |
NA_escape, adrenergic escape according to norepinephrine cut-off; ADR_escape, adrenergic escape according to epinephrine cut-off; 6MWT, 6 min walk test; LVEF, left ventricular ejection fraction; HR, heart rate. For continuous variables, the HR is that associated with a unitary increase in the variable.
Figure 1.
Three-year survival of patients grouped according to adrenergic escape status as established using norepinephrine cut-off. Patients in adrenergic escape, defined by norepinephrine levels above the upper limit of normal, showed worse survival than patients not in adrenergic escape.
In bivariate analysis of the two hormones, only the presence of adrenergic escape for norepinephrine but not for epinephrine retained independence of one from the other. Furthermore, adrenergic escape for norepinephrine remained a statistically significant predictor in a common multivariate analysis, which included those risk markers that were identified in univariate analysis as described above (see Table 3).
Table 3.
Multivariate Cox proportional hazard models for all-cause mortality
| HR | 95% CI | Chi2 | p- value | |
|---|---|---|---|---|
| NA_escape | 1.915 | 1.387–2.645 | 15.60 | <0.0001 |
| NYHA | 1.994 | 1.506–2.511 | 26.01 | <0.0001 |
| NT-proBNP (100 pg/mL) | 1.011 | 1.005–1.016 | 15.96 | <0.0001 |
| 6MWT (m) | 0.997 | 0.996–0.999 | 15.69 | <0.0001 |
| LVEF (%) | 0.959 | 0.924–0.995 | 4.84 | <0.05 |
| ADR_escape | 1.386 | 0.965–1.991 | 3.13 | 0,08 |
| HR (b.p.m.) | 1.002 | 0.998–1.007 | 0.95 | 0,33 |
NA_escape, adrenergic escape according to norepinephrine cut-off; ADR_escape, adrenergic escape according to epinephrine cut-off; 6MWT, 6 min walk test; LVEF, left ventricular ejection fraction; HR, heart rate. For continuous variables, the HR is that associated with a unitary increase in the variable.
Discussion
The present study sought to establish whether and to what extent adrenergic escape occurs in stable CHF patients on chronic stable β-blocker therapy and whether it has any prognostic relevance. The main findings of this prospective, observational study are:
Irrespective of the individual β-blocker agent and the dose equivalent taken, about one-third of patients with stable CHF present with adrenergic escape, as defined by norepinephrine levels above the upper limit of normal for the reference laboratory.
Inclusion of measurements of epinephrine in addition to norepinephrine does not enhance the definition of adrenergic escape.
Mean resting heart rate does not appear to represent an adequate surrogate for adrenergic escape, as neither norepinephrine levels nor the presence of adrenergic escape correlates with it.
The presence of adrenergic escape under chronic stable β-blocker therapy represents a strong and independent indicator of adverse clinical outcome.
Even though conflicting results regarding the influence of β-blockers on catecholamine levels have been reported in the past,8–14 to the best of our knowledge, very little is known about the issue of chronic adrenergic escape, including its possible prognostic relevance in CHF patients on chronic stable β-blocker treatment. This is important because complete sympatholysis during the titration phase has been shown to have possible detrimental effects.20 The main advantage of the present study is that it reports ‘real world data’ on patients from a university outpatient department, which might enhance the clinical transferability of the data, compared with the results from randomized trials.
Although the concept of hormonal escape has not been addressed as such for adrenergic activity, reports21,22 on the RAAS indicate that as many as 40% of patients present with elevated hormonal levels despite chronic ACE-inhibitor therapy, which does not appear to be fully reversible by the addition of an ARB.19 ACE-inhibitors counter RAAS activity at hormone formation; however, the mode of action of ARBs, which is comparable to β-blockers, is blockade of hormonal receptors. This in return bears similarities to adrenergic escape to β-blockers, as catecholamines are the effectors of the sympathetic nervous system and β-blockers aim at reducing sympathetic activity. Furthermore, as RAAS escape has been described via angiotensin ratios,2 a certain similarity can be noted. It is, therefore, interesting to note that there was a similar proportion of patients in hormonal escape for each of these neurohumoral axes when comparing the above studies for aldosterone escape to our study for adrenergic escape.
We found no relation between the choice of β-blocker and the occurrence of adrenergic escape. There is ongoing controversy as to whether individual β-blockers influence levels of norepinephrine, and if so, to what extent and in which direction.8–14 It was hypothesized23 that differential inhibition of β1- and β2-receptors may account for a possible differential effect on hormonal levels. Most of the aforementioned studies investigated the short-term effects of newly commenced or titrated β-blocker treatment; however, it was recently demonstrated14 that chronic stable β-blocker treatment significantly lowered adrenergic activity irrespective of the agent chosen. This would support the present finding of equality of β-blockers with regard to hormonal markers of adrenergic activity.
β-Blockers do not suppress the formation of norepinephrine, they indirectly act on hormonal levels through modulation of background sympathetic activity. Therefore, our finding of an equal distribution of adrenergic escape throughout the range of dose equivalents taken appears possible. In fact, similar to our findings for adrenergic activity, failure to suppress aldosterone levels even with maximum doses of ACE-inhibitors or addition of an ARB have been described2,19 for RAAS activity. Furthermore, our findings indirectly support the reports that individual patients may have different responses to β-blocker therapy24 and that even at lower doses, β-blockers will exert a beneficial effect on mortality.25 It may well be that characterization of these sub-cohorts might be achieved by consideration of adrenergic escape.
It does, however, come as a surprise that heart rate does not appear to represent a good surrogate marker for adrenergic escape, as titration of β-blockers is commonly performed with respect to heart rate.26 On the other hand, according to our data, norepinephrine represents a stronger marker for adrenergic escape than epinephrine, both with respect to statistical power and independence of one neurohormone from the other. This is consistent with previous reports14 demonstrating superiority of norepinephrine over epinephrine in terms of both prognostic power and accuracy. As norepinephrine shows preponderance for α-adrenoceptors, and heart rate is predominantly mediated through β-adrenoceptors; this would explain the lack of statistical association between heart rate and adrenergic escape. It would also be consistent with findings that the benefits with, e.g. metoprolol, were independent from the change in heart rate achieved.27 However, heart rate remains a simple bedside marker of disease severity and the fact that it correlated with catecholamine levels in patients who were not receiving β-blockers further substantiates the theory of uncoupling of catecholamine levels and activity during β-blocker therapy.
Despite the fact that both epinephrine and norepinephrine as continuous variables failed to gain statistical significance in univariate analysis, the presence of adrenergic escape represents a strong indicator of adverse outcome, independent from other established risk markers. For the β-blocker titration phase, Bristow et al.20 showed that baseline norepinephrine levels were associated with a progressive increase in mortality that was independent from treatment group. Similarly, Vantrimpont et al.4 demonstrated for ACE inhibition that patients who maintained norepinephrine levels at the upper limit of normal were at increased risk for study events. It thus appears conceivable that chronic stable β-blocker treatment, as opposed to the titration phase, blunts the prognostic relevance of norepinephrine levels as such, effectively dividing patients into those with response to treatment and those without. This would be in line with previous reports from our group.14
On the other hand, despite the fact that haemodynamics were comparable between groups, that there was no relation between dose equivalent and presence of escape and that escape was independent from other markers of severity in multivariable analysis, to a certain extent our findings support the concept that patients in escape are more severely ill and therefore present with elevated hormonal levels. It is therefore not entirely clear whether catecholamine levels were elevated simply due to a more advanced stage of heart failure or whether it was due to lack of treatment efficacy as indicated by adrenergic escape that lead to more pronounced symptoms and signs.
We were able to demonstrate the risk associated with elevated hormonal levels despite treatment directed at lowering these levels—in other words, escape to treatment. This goes beyond the simple association of increased risk with increased hormonal levels. Indirectly, and in that respect less directly associated with the idea of RAAS escape, this concept of neurohumoral control would be the baseline assumption for other neurohumoral titration strategies such as (NT-pro)BNP control for dose titration, too. This further strengthens the notion of verification of treatment efficacy via effector hormones but as the prognostic power of adrenergic escape was independent from NT-proBNP, and since hormonal levels were only mildly correlated, adrenergic escape cannot be estimated via determination of NT-proBNP.
As a consequence of the above, it is hormonal response to treatment, represented as adrenergic escape, which should be considered as an adverse indicator rather than individual levels of norepinephrine. A clinical consequence could be a more aggressive attempt at neurohumoral control, possibly by the introduction of a third or even a fourth neurohumoral modulator into the treatment regime. This, however, would have to be tested in a prospective, controlled trial. Potentially, our results could help to identify those patients with CHF that might benefit from more aggressive/extensive medical treatment especially in the setting of existing medical combination therapy. We would therefore not consider adrenergic escape as a supplement to the existing list of prognostic markers as such, but would advocate the determination of adrenergic escape in a situation where failure of existing, maximally titrated therapy is suspected, in order to aid clinical decision-making regarding extension of treatment options.
Limitations
We cannot completely exclude a certain pre-selection bias. Recruitment depends on referring physicians deeming their patients appropriate for attendance at our university hospital clinic. Also, our patients reflect the average population at a tertiary referral centre, which accounts for the low proportion of ischaemic cardiomyopathy and the high percentage of males in this study. Consequently, our results might not be fully transferable to primary care patients and women. However, since tertiary care centres are where risk evaluation towards more aggressive treatment options takes place and since we recruited from our daily clinic, we would still be inclined to call it ‘real-world data’ as opposed to a population from a randomized trial. Furthermore, determination of plasma catecholamines is highly dependent on meticulous pre-analysis preparation. We tried to diminish this effect by using a strict protocol including a 30 min rest period before blood sampling from an indwelling catheter and immediate processing. Since we did not test catecholamines before the initiation of treatment, the association between AE and survival is correlative, not necessarily causal. To test this hypothesis, another study would be needed, though our results would appear to support this theory. Also, we cannot differentiate primary inefficacy to suppress hormonal levels from secondary failure to keep hormonal levels suppressed during the time period following initiation of treatment. Both will result in elevated levels despite treatment. As a consequence of the above limitations, we consider our data as hypothesis generating rather than definite proof.
Conclusion
Adrenergic escape appears to be present in about one-third of CHF patients on chronic stable β-blocker therapy irrespective of the individual β-blocker agent used and the dose equivalent. Heart rate does not represent adrenergic escape. Since adrenergic escape is a strong and independent indicator of adverse clinical outcome that potentially indicates response to existing treatment, determination of adrenergic escape could be used to help identify those CHF patients that might benefit from more aggressive/extensive medical treatment.
Funding
This study was supported by a grant from the Carl-Baresel-Foundation, Stuttgart, Germany (www.carl-baresel-stiftung.de).
Acknowledgements
The authors are indebted to Ms Karen Slottje and Ms Karin Hornig for their most valuable help with data acquisition and management during the course of the study.
Conflict of interest: none declared.
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