1
2 Table of contents
Abstract... 6
I. Introduction ... 8
I.1. The prognosis of CHF ... 8
I.2. Prognostic stratification in CHF ... 10
I.3. The role of natriuretic peptides in the prognostic evaluation of CHF ... 19
I.3.1. Biology and physiology of natriuretic peptides ... 19
I.3.2. The role of the natriuretic peptides in the diagnosis of heart failure ... 22
I.3.3.The prognostic significance of the natriuretic peptides ... 24
I.4.The role of the six minutes walking test in the prognostic evaluation of CHF.28 I.4.1. The exercise tolerance in CHF ... 28
I.4.2. The six minutes walking test: introduction ... 31
I.4.3. Determinants of the 6MWT and use of a reference equation ... 33
I.4.4. Indications for a 6MWT according to ATS guidelines. ... 34
I.4.5. The problem of reproducibility and the safety of the test ... 35
I.4.6. The prognostic significance of the 6MWT ... 36
I.4.7. The 6MWT in the evaluation of the effectiveness of the therapy ... 38
II. Aim of the study... 40
III. Materials and methods ... 41
III.1. Study population and clinical assessment ... 41
III. 2 Echocardiography ... 42
III. 3. Six minutes walking test ... 43
III. 4. Statistical analysis ... 44
IV. Results ... 46
IV. 1. Patients characteristics ... 46
IV. 2. ROC analysis ... 49
IV. 3. Cox regression analysis: predictors of all cause death ... 52
3 V. Discussion ... 56 VI. Conclusions ... 63 Bibliography ... 64
4 Abbreviations and acronyms:
ACCF/AHA= American College of Cardiology Foundation /American Heart Association
ACEi = Angiotensin Converting Enzyme Inhibitor ADHF = Acute Decompensated Heart Failure ANP = Atrial Natriuretic Peptide
ARB = Angiotensin Type 1 Receptor Blocker ATP= Adenosine TriPhosphate
AUC= Area Under the Curve BB = Beta Blocker
BNP = B-type Natriuretic Peptide CHF = Chronic Heart Failure
CHFpEF= Chronic Heart Failure with preserved ejection fraction CHFrEF= Chronic Heart failure with reduced ejection fraction COPD= Chronic Obstructive Pulmonary Disease
CPET= CardioPulmonary Exercise Test CO= Cut Off
EDT = E Wave Deceleration Time ESC= European Society of Cardiology EDV=End Diastolic Volume
ESV= End Systolic Volume HF= Heart Failure
HFSS= The Heart Failure Survival Score ICD= Implantable Cardioverter Defibrillator LVEF = Left Ventricular Ejection Fraction MRA = Mineralocorticoid Receptor Antagonist
NYHA = New York Heart Association
5 NT-proBNP = N-Terminal pro Brain Natriuretic Peptide
PRA= Plasma Renin Activity
ROC= Receiver Operating Characteristic RV = Right Ventricle
TAPSE = Tricuspid Annular Plane Systolic Excursion TIA= Transitory ischaemic attack
6MWT = Six Minutes Walking Test 6MWD= Six Minutes Walking Distance
6
Abstract
Background. Prognostic stratification in chronic heart failure (CHF) is a complex process that may help guide therapeutic decision making. Natriuretic peptides (NPs) and the six minutes walking test (6MWT) proved to be valid prognostic markers in chronic heart failure.
Aims. In the present study, we sought to investigate the prognostic value of exercise tolerance as assessed by 6MWT in patients with both CHFrEF and CHFpEF. To gain information in the outcome prediction patients were further characterized according to their BNP values.
Materials and methods. We analysed 616 patients with stable chronic heart failure (mean LVEF 42%, 221/616 with preserved ejection fraction). The patients underwent a 6MWT, BNP was measured within 7 days from the date of the walking test. A complete physical examination, an EKG and an echocardiography were performed the day of the walking tests. Patients were followed up for a mean period of 60 months for the end point of all-cause mortality. The cut off levels of the 6MWT and BNP were determined at the ROC analysis. Survival rates were analyzed with the Kaplan Meier method. The strength of association between BNP and 6MWT and long-term mortality was assessed by means of univariate and multivariate Cox regression models.
7 Results There were 76 deaths during a mean follow up of 60 months. According to the results of the 6MWT, at 60 months there was a significant difference in the survival of patients with a 6MWT lower than a cut-off of 323 meters ( rate of survival = 64% ) compared to the patients above the cut-off (rate of survival = 87%) ( Chi square log-rank test = 24.4, P < 0.0001). Adding the values of BNP we obtained an even more significant stratification.The patients were stratified into four groups according to BNP values and distance walked at the 6MWT. The survival rates at 60 months were : 31% for the group with BNP >330 pg/ml and 6MWT<323 meters, 68% for the group with BNP >330 pg/ml and a 6MWT >323 meters, 82% the group with BNP <330 pg/ml and 6MWD <323 meters and 92 % for the group with BNP<330 pg/ml e 6MWT >323 meters. (Chi-square logrank 103, P <0.0001).
Conclusions : Among the patients with a reduction of the exercise tolerance (documented by a 6MWT < 323 meters) those with higher levels of BNP ( > 330 pg/ml) have the worst prognosis. An approach based on the combined results of the 6MWT and BNP levels can provide valid prognostic information in patients with CHF.
8
I Introduction
I.1 The prognosis of chronic heart failure
Chronic heart failure (CHF) is defined as complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood1.Despite the advances in its therapy and management, it is still a disease with a poor prognosis and a high mortality rate. In the Framingham Study, the median survival was 1.7 years for men and 3.2 years for women, with only 25% of men and 38% of women surviving 5 years. More recent meta-analyses, even if ascertained a slightly higher survival rate, confirmed a poor prognosis both for heart failure with reduced ejection fraction and for heart failure with preserved ejection fraction2. Although survival has improved, the absolute mortality rates for CHF remain approximately 50% within 5 years of diagnosis3, 4 . As such overall mortality rate can be considered equal or even higher than that of many cancers, including those involving the bladder, breast, uterus, and prostate 4, 5 . In fact in a swedish study involving a large population 4, HF was associated with an unadjusted case fatality rate of 59% at five years, while that of the most common cancers (lung, colorectal, prostate, bladder, breast and ovarian cancers) combined was 58% .
CHF is also a condition characterized by a high rate of hospitalization and short term readmission after a first hospitalization (almost 25% of patients
9 are readmitted within three months ) with a consequent significant economic impact6. Given those characteristics, an accurate risk stratification could play a central role in the management of CHF patients, and may help guide therapeutic decision- making, including a more rapid transition to advanced HF therapies when necessary. 7
Establishing a prognosis is a complex process that cannot rely only on the clinical judgement, as it has been observed in some studies that underline the physician's inaccuracy in prediction of risks 8 9.
As such it seems that developing an objective and easy- to- perform measurment of the patient risk, may result in a useful tool for the physician, and in the following chapter we will analyze the prognostic markers previously studied for CHF and the reliable methods to perform a prognostic stratification
10
I.2 Prognostic stratification in CHF
Many variables provide prognostic information in the evaluation of CHF, and this topic has been deeply investigated by several studies.
A statistical study based on The Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity (CHARM) database analyzed several clinical readily available characteristics and their impact on prognosis, focusing on cardiovascular death, hospitalizations for worsening HF and all-cause mortality10. It was found that the most powerful predictor of cardiovascular death or CHF hospitalization is age, with a non linear relationship, since age had relatively little impact on outcome until the age of 60, with a subsequent two fold increase every 10 years. The same study underlines the importance of reduced left ventricular ejection fraction (LVEF) and diabetes as predicting factors both for cardiovascular and all-cause death. Diabetes was associated with around a doubling of risk of death in those patients. Other important characteristics related to a poor prognosis emerging from the CHARM study were: previous hospitalizations for worsening HF, low body mass, cardiomegaly on chest X-ray, low diastolic blood pressure, prior myocardial infarction, or other indicators of ischaemic aetiology. Other authors have analyzed the considerable impact of renal insufficiency on the prognosis of CHF 11 . This is particulary remarkable considering the high prevalence of renal impairment in patients with CHF; at least a mild degree of renal
11 impairment is present in about 50% of stable HF outpatients and these patients represent a high-risk group with an approximately 50% increased relative mortality risk when compared with patients who have a normal renal function. Diabetes and renal insufficiency are not the only non-cardiac comorbidities affecting the prognosis of the CHF patients: in a relatively recent population study12, a considerable number of hospitalization and deaths in these patients was attributed to pulmonary comorbidities, such as COPD and other lower airway respiratory diseases, to psychiatric conditions such as depression or other affective disorders, and to arterial hypertension12. Another important observation of this study is that only 4% of the patients had CHF alone and 39% of CHF patients had 5 noncardiac comorbidities. Regarding CHF rehospitalization risk, comorbidities may impact by causing, exacerbating, or masking CHF, or by affecting compliance or health careseeking behaviors.13
Many aspects of the echocardiogram, beside the above mentioned reduced LVEF, correlate with mortality in CHF, including left ventricular end-systolic volume (EDV) and stroke volume 14, mitral and tricuspid insufficiency 15, right ventricular systolic dysfunction 16, impaired peak early- (E) to late- (A) mitral diastolic flow ratios (E:A ratios), and impaired peak early-diastolic mitral filling velocity to peak early-diastolic mitral annular velocity (E:E' ratio).17
12 functional capacity is an important prognostic factor18. The NYHA class has long been used as a simple, widely recognized metric of a patient's exercise capacity, although there is significant physician and subject inconsistency in its reporting 19, with a high interoperator variability 20. Given the subjective nature of the NYHA class, more quantitative methods of assessing functional capacity are needed, of which the gold standard is represented by the cardiopulmonary exercise test (CPET) ; strong evidence exists to support the prognostic value of the CPET, in particular regarding patients who are being considered for heart transplantation 21. Other studies
22
confirmed the prognostic power of the peak VO2 determined with a CPET, identifying peak VO2 as the most significant predictor of cardiac death among all other clinical and haemodynamic parameters22. However, it should be emphasized that the cardiopulmonary exercise test is not frequently used in mild to moderate chronic heart failure ambulatory patients, for several reasons, including the limited availability of equipment and the inability of patients to perform a maximal effort test 23. In Italy it is estimated that approximately 70% of patients with heart failure, are not referred to cardiology departments, but to departments of internal medicine, where facilities for a cardiopulmonary test are rarely available, and CPET may be performed in about 5% of the patients24 . In this context, the six minutes walking test (6MWT) has gained popularity as a valid alternative of the CPET, especially regarding the predictivity of adverse
13 outcome 25 26 27, being less expensive and easier to perform than the CPET, thus easier to propose, despite its limits, as a first line screning for evaluating exercise tolerance and prognosis in clinically stable CHF patients. The evidences about its potential role in the prognostic stratification of CHF clinically stable patients will be discussed in detail in chapter I.3.
Beside the above mentioned clinical and echocardiographic features, a considerable amount of biomarkers and laboratory parameters were investigated as prognostic markers in CHF : the natriuretic peptides are surely the most investigated markers, and their role will be discussed in detail the following chapter (see chap.I.2). Other prognostic biomarkers reffered in literature are inflammatory markers, such interleukin-6, C-reactive protein, and tumor necrosis factor α, and a decreased lymphocyte count or a elevated leukocyte count, elevated uric acid, low cholesterol, hypoalbuminemia, and anemia.
Surely there is a consistent body of literature investigating this matter, and several parameters were taken into account in different studies; the most recent systematic review that tries to summarise this topic, and to reveal the strongest predictors of death was conducted by Rahimi et al 28. The authors found that among different types of factors, including sociodemographic conditions (age, gender), clinical and instrumental features (New York Heart Association functional class, diabetes,
14 weight/body mass index, hyponatremia), and comorbidities (renal insufficiency), two variables that emerged as consistent and strong predictors of risk of death were : BNP (or NT-pro BNP) level, and exercise capacity.
While several independent prognostic variables have already been validated, their association in multivariable risk scores may be useful, as supported by the current ACCF/AHA guidelines for the management of heart failure. Many scores have been established to determine an accurate prognostic stratification, of which the "Seattle heart failure model29 " is probably the most used ; this model takes into account several parameters, including demographic variables (age, gender), medications, clinical features ( NYHA class, aetiology, EF,blood pressure) and laboratory parameters ( sodium level, creatinine, uric acid, cholesterol, haemoglobin, white blood cells, % of lymphocites). Of note, in establishing this score the authors found a strong and direct correlation between mortality and diuretic dose; the calculated daily diuretic dose per kilogram of body weight was found to be the most powerful univariate predictor of mortality, with a 30% increase in risk of death for each 1 mg/kg per day.
Another widely used score is the Heart Failure Survival Score (HFSS) 30, that was the first multivariate heart failure model to be derived in one patient population and prospectively validated in another heart failure population. Variables included are ischemic aetiology, LVEF, mean blood
15 pressure, heart rate, a QRS width of 120 milliseconds or more, serum sodium, and peak VO2 at the CPET. The model divides patients into low, moderate and high risk groups. The requirement for peak VO2— rarely measured outside the setting of evaluation for cardiac transplantation candidacy—limits its application.18
Although these risk scores are indicated in the ACC-AHA guidelines, a recent systematic review on these models shed light on their limits, affirming that heart failure risk score models showed inconsistent performance and demonstrated modest discrimination and questionable calibration31. Furthermore, the previously cited score models were derived from a cohort of patients carefully selected for a randomized clinical trial over 20 years ago, with its inclusion and exclusion criteria, and serum biomarkers for patient risk stratification were not available 32 .
Other scores were further developed; as previously discussed, the comorbidities play a central role in the prognosis of CHF, thus Senni and coworkers 33 determined a new score called "Cardiac and Comorbid Conditions " (3C-HF) that took into consideration manifold comorbities, beyond cardiovascular well established parameters such as LVEF and NHYA class . The comorbidities that resulted more powerful in predicting prognosis were diabetes, renal dysfunction, anemia and hypertension.
There also have been developed risk scores that included biomarkers, in particular in the new score called Barcelona Bio-Heart Failure Risk
16 Calculator 32, that contains a combination of well known clinical and echocardiographic risk factors and three biomarkers (NT-proBNP, troponin T and high-sensitivity soluble ST2) ; this score better predicts death if compared with the previous models that do not oncorporate biomarkers.
Another recent score is the" Metabolic exercise test data combined with cardiac and kidney indexes" (MECKI SCORE) 34, that incorporates data from the cardiopulmonary exercise test (peak oxygen consumption [% pred] and VE/VCO2 slope) with clinical easy-to-obtain variables ((hemoglobin, Na+, kidney function by means of MDRD) and LVEF.
As discussed above, different ways of estimating the risk in chronic heart failure were developed, mainly using integrated scores; however, it has become clear, as underlined by Mantegazza and coworkers in a recent review35, that their clinical use is often limited to specific settings, and frequently based on expensive or not easy available parameters, such as the results of a cardiopulmonary exercise test. Thus we can suggest that an approach based on the evaluation of functional capacity with a simple and well tolerated test, such as the 6MWT, combined with a biomarker of proven predictive value ( the natriuretic peptides) could be able to give an appropiate knowledge of the risk of the CHF patient, useful as a first line risk screening of the CHF outpatients, without having to resort to less available parameters.
17 The correlation between BNP levels and the distance walked in a six minutes walking test has already been studied in two relatively small studies; Hogenhuiss et al 36 pointed out that BNP levels and 6MWT distance could represent different aspects of the clinical syndrome of CHF, with the BNP plasma levels being more related to measures of cardiac function, such as LVEF, while 6MWT reflects functional capacity and quality of life. Moreover in this study, BNP levels were not associated with the distance walked. In another study Wieczorek et al 37, analysing a cohort of 46 patients with CHF, noted that the there is a significant association between these two parameters, finding that the BNP concentrations were inversely correlated with the 6-min walk distances. Furthermore the authors noted that the two patients who died of progressive heart failure during the follow up period of the study, and the other two patients who underwent cadiac transplantation, all had high BNP concentrations (median 1080 ng/l) and walked short distances (median 183 m). As it will be discussed in the folllowing chapters, both the 6MWT and the BNP concentration are valuable indicators of disease severity, but there are situations where an approach based on the combination of these two parameters might be advantageous. The presence of arthritis or a previous stroke, for example, may preclude a precise evaluation of a heart failure patient with the walk test. In addition, the objectivity of the BNP concentration avoids the variability in the 6MWT that can result from different factors, as will be
18 discussed in the chapter I.4.
In the following chapters we shall present the biology of the natriuretic peptides and their role in the management of CHF patients, focusing mostly on their role as prognostic markers. We shall also analyse the usefulness of the 6 minutes walking test in the evaluation of functional capacity, and its role as a prognostic predictor, according to the studies available in the literature.
19
I.3 The role of natriuretic peptides in the prognostic evaluation
of CHF
I.3.1Biology and physiology of the natriuretic peptides
The B-Type Natriuretic peptide (BNP) was first discovered in the brain of pigs in 1988, but soon it became clear that the predominant cells where it was synthesized were the cardiomyocites38. The biochemical structure of BNP consists of a single peptic chain with a ring closed by a cysteinc legam. In physiological conditions, the largest part of BNP molecules seems to be produced in the atrial myocardium, but, unlike the ANP, BNP is not retained in specific granuli39. On the contrary, in conditions of haemodynamic over-load BNP is mostly produced by ventricular cardiomyocites. In fact, it has been demonstrated that the gene codifying BNP is expressed in the cardio-myocites of rats within 24 hours from the application of a stretching on the membrane of those cells. As such, stretching of the left ventricular myo-cardium, due to volume or pressure overload states, sodium and water reten-tion, and in general the haemodynamic congesreten-tion, is considered the main inducement of the production and release of BNP. In vivo the expression of the BNP's gene is induced within an hour from the beginning of the overlo-ad39. Therefore, elevated blood BNP and NT-proBNP levels occur in the set-ting of elevated filling pressures in patients with cardiac dysfunc-tion,particulary in heart failure, and can provide relatively reliable diagnostic and prognostic information40. On the other hand, NP values are secreted in
20 increased amounts not only in HF, but in different conditions (such as pul-monary embolism and pulpul-monary hypertension, atrial fibrillation, renal fail-ure) as well41. In patients with CHF, it has been observed that the levels of BNP's m-RNA remains constantly high. Moreover some studies suggest that hypertrophy, ischaemia and fibrosis of the ventricular myocardium can stimulate the secretion of BNP42 43. Mechanical stress is not the only mechanism involved in BNP stimulation; in fact elevation of angiotensin II and endothelin levels are strongly associated with an increase in BNP's pro-duction. Other molecules are also involved, such as cathecolamines, gluco-corticoids and some cytochines 39. After the expression of the specific gene, BNP is synthesized as a propeptide (preproBNP), then converted into the proBNP that is released into the circulation; further processing of this mole-cule results in the active molemole-cule, called BNP, and an inactive N-terminal fragment of proBNP called NT-proBNP.44
The two main effects of BNP are vasodilation and stimulation of sodium and water excretion 45.These effects are due in part to a direct stimulation of type A and B natriuretic peptides's receptors, that are widely distrubuted in the organism, mostly on tubular renal cells and vascular smooth myocites, in part depends on the inhibition of many vasocostricting hormones, such as angiotensin II, aldosteron, cathecolamines, vasopressin, endothelin45. It can be deduced that BNP acts like a counterregolatory hormone that tend to
21 balance the excess of sodium and water retention and the vasoconstriction typical of the patophysiology of CHF.
Moreover some studies have shown that there can also be cardiac effects of BNP, that seem to improve the diastolic function with un unclear mecha-nism46. The clereance of BNP molecules is in part related to a process of degradation into the cells, after its intenalization via the type C BNP re-ceptor ( also called " clereance rere-ceptor"), in part is put in place in the plasma by non-specific endopeptidases. In addition, a small part is cleared by the kidneys44, 47. The metabolism of the NT-proBNP and that of BNP is slightly different, because even if both of them are cleared by the kidneys, only the BNP molecules are cleared by endopeptidases and internalized into the cells; this results in a longer half-life of NT-proBNP molecules ( 120 minutes, compared to 20 minutes of BNP) and in different range levels of normality 44.
22 I.3.2 Role of the natriuretic peptides in the diagnosis of heart failure
According to ESC current guidelines the diagnosis of heart failure is based on clinical signs and symptoms rather than on single test results; however, these guidelines underline the fact that the most common symptoms and signs of heart failure, like dispnea and ankle oedema, are not specific for heart failure and occur in different conditions as well; on the other hand the more specific findings and symptoms, such as elevated jugular venous pres-sure and displacement of the apical impulse, are harder to detect and, there-fore, less reproducible. In this context is placed the attention to the role of natriuretic peptides in the discrimination of patients with a more probable cardiac aethiology of their symptoms, both for patients presenting with an acute onset and for those presenting with milder symptoms.The ESC guide-lines highlight the fact that a normal natriuretic peptide level in an un-treated patient virtually excludes significant cardiac disease, making an echocardiogram unnecessary. In an acute setting of a patient presented to clinical attention with dyspnea, the current cut-off levels to rule out heart failure are considered to be a NT-proBNP lower than 300 pg/mLb or a BNP lower than 100 pg/mLb 41 1, 48.In chronic settings the cut off levels taken into account to rule out heart failure are lower, being respectively 125pg/ml and 35 pg/ml. Moreover, it has been demonstrated that the values of plasma BNP can represent an objective assesment of NYHA class during chronic treatment of heart failure. It has been found that BNP decreases in
23 patients whose NYHA class improves during treatment .This corrrelation has shown to be superior to the one that links common measurements of systolic function, such as LVEF, to the NYHA class49.
24 I.3.3 The prognostic significance of the natriuretic peptides
The utility of the BNP values in the prognostic stratification of CHF pa-tients has been well established, up to the point that the current AHA/ACC guidelines include the BNP measurment as a class I recommendation in es-tablishing prognosis or disease severity in CHF, with a level of evidence "A". Indeed there are many studies supporting the idea that natriuretic peptides are a useful tool in prognostic stratification both among patients with heart failure, or even those without history of heart failure. In this last category, Wang et al demostrated that plasma natriuretic peptide levels pre-dict the risk of all cause death, of cardiovascular events, of new onset of atrial fibrillation and of stroke or TIA50. Others highlighted the role of BNP in predicting the prognosis in patients dismissed after an acute coronary syndrome 51 and acute pulmonary embolism 52. Regarding HF, natriuretic peptides have been investigated as prognostic markers in different clinical settings, including population at risk of developing heart failure, patients with stable chronic heart failure and those with acute decompensated heart failure. It can be noted that natriuretic peptides are are equal or even more accurate in predicting prognosis of CHF patients than clinical scores or other biomarkers. In fact, the prognostic relevance of BNP levels was found to be equivalent in risk stratification to the Heart Failure Survival Score when evaluating ambulatory patients53, with the advantage that it does not require a a specialistic test such as the cardiopulmonary test, rarely
per-25 formed outside the setting of evaluation for cardiac transplantation candi-dacy. Furthermore, the Heart Outcomes Prevention Evaluation Study (
HOPE)54, evaluating a population with previous main cardiovascular events, underlined that NTproBNP is, among different biomarkers, including 9 inflammatory biomarkers (Plasma sICAM-1, IL-6, sTNF-R-1 and - sIL-1Ra, sVCAM-1 andIL-18 ) and microalbuminuria,the only biomarker provid-ing incremental information above that obtained by models of traditional risk factors. In a study based on a large population (4300 patients, Valsartan heart failure trial) 55 natriuretic peptides levels were validated as a powerful predictor of poor outcome even taking into account demographic, clinical and echocardiographic markers of risk in HF; as such the BNP levels could add important informations regarding the risk stratification, even among pa-tients with similar demographic, clinical and echocardiographic characteris-tics. In this study the predictive value of BNP was found to be superior to that of other neurohormones like norepinephrine, aldosterone, endothelin and PRA.There are several other papers about the role of BNP in the prog-nostic statification of CHF patients: Berger et al, pointing the attention to the BNP as a predictor of sudden death in CHF, discovered that among dif-ferent risk factors of sudden death in CHF patients, including LVEF, ANP, endothelin, NYHA class and systolic blood pressure, BNP level was the only independent predictor of sudden death. 56
26 Given the high incidence of sudden cardiac death in CHF patients, NPs might be useful in evaluating the option of implanting an ICD. In fact, Verma et al found that determining BNP levels prior to the implantation of an ICD can predict future appropriate therapies from the defibrillator itself57.There have also been studies advocating the role of blood natriuretic peptide testing in selection for cardiac transplantations58, 59;
the authors found thatin the setting of advanced CHF a single measurement of NT-proBNP can help to identify patients at highest risk of death, and is a better prognostic marker than the LVEF, pVO2 or HFSS58.The natriuretic peptides have also proven to be a useful tool for the general practitioner, both for diagnosis and for risk of death stratification; in fact Gustafsson et al have found that NTproBNP levels higher than 125pg/ml correlate with a higher mortality rate among primary care patients referred to the general practitioner for echocardiographic evaluation in the suspect of CHF60. Clinical utility of BNP in a stable outpatient setting has been proved even as regards the risk of decompensation and re-hospitalizations, among sta-ble patients with non ischaemic dilative cardiomyopathy ( NHYA class 1 and 2) by Nishii et al, who found that the BNP values six months after the discharge for a first decompensation predicted the risk of rehospitalization for decompensated HF and of sudden death, better than several echocardio-graphic parameters61. Moreover even the values at the day of the discharge can predict the risk of rehospitalization ; high predischarge BNP values are
27 a strong, independent marker of death or re-admission after decompensated CHF, more relevant than common clinical or echocardiographic parameters and more relevant than changes in BNP levels during acute cares62. Thus, we can conclude that NPs are a well established prognostic marker for CHF patients, and in the near future it is possible that a therapy guided by their levels will play a central role in the treatment of CHF, as it will be dis-cussed in the following chapters.
28
I.4 The role of the six minutes walking test in the prognostic
evaluation of CHF.
I.4.1 The exercise tolerance in CHF
The reduced exercise tolerance represents one of the clinical features of main relevance CHF syndrome, so that it is included as an essential part in one of the definitions of CHF : "CHF represents a complex syndrome char-acterized by alterations in the left ventricular function and in the neuro-hormonal regulation, which correlates to exercise intolerance, water reten-tion and reduced longevity" 63. Some studies64 suggest that the central haemodynamic parameters correlate scarsely to the reduction in the exercise capacity, while such function is mainly invalidated by alterations in the pe-ripheral circulation . The functional limitation correlates on one side with the so-called “fatigue” of the skeletal muscles, and on the other with dispnea on exertion64. The fatigue is associated partially with a reduced muscle blood flow and abnormalities in muscle metabolism. In fact the skeletal muscle, in CHF, shows some important modifications, in its mass, structure, blood-stream an intrinsic metabolic capacity65. Dyspnea on exertion results from different mechanisms, mainly related to an increase in capillary wedge pres-sure, increased dead space, peripheral muscle underperfusion and conse-quently respiratory muscle fatigue64.Nevertheless, the noticing of hyper-oxemia and hypocapnia at the emogasanalysis during the exercise sug-gested that such values originate from a hyperventilation mechanism, and
29 that every abnormality in the breathing function in patients with CHF is secondary to modifications that take place elsewhere66. In fact recently it has been developed the "skeletal muscle hypothesis"65 , that suggest a peripheral origin of symptoms in CHF. It has been observed that the excess of neuro-hormal and sympathetic activation cause a a restraint of the blood flow to the skeletal muscle that, together with the metabolic and structural abnor-malities in the skeletal muscle of CHF patients, is able to trigger an exces-sive activation of the ergoreflex, a peripheral reflex originating in the skele-tal muscle sensitive to products of muscle work. The overactivation of this reflex determines an exaggerated ventilatory response, and directly stimu-lates sympathetic activation, which, in the short term, has the beneficial ef-fect of vasocostricting the non exercising limbs, but in the long term results to be maladaptive, contributing to mantain the vasoconstrictor milieu that concurs to the progression of the disease.
Exercise tolerance has always been considered a basic feature to evaluate in patients with CHF, up to the point that the widely used New York Heart Association classification is based precisely on the symptoms, mainly in re-lation to daily-life activities, that involve a certain “exertion”. The reduced exercise tolerance, in fact, is not only a characteristic that reduces quality of life, but also results in being an important predictor of poor prognosis, and thus mortality. In fact the mortality ratio at 1 year is only 5%-10% in patients with class NYHA2, while this ratio raises to 30%-70% in patients
30 with class NYHA4 67. However, as we have already discussed, NHYA class is subjective, lacks of sensitivity and there is significant physician and subject inconsistency in its reporting, with a reproducibility of about 55%-60%19 20, 68. Other studies highlight the way exertion symptoms perceived by patients can correlate with the maximum exercise capacity, yet often un-derestimate the functional disability, which should therefore be evaluated with objective maximal exertion tests, the golden standard of which is rep-resented by the cardiopulmonary exercise test69.We have already discussed the problems related to the pratical application of this test, and how the 6MWT seems to provide similar information, and in this chapter we shall analyze in detail the characteristics of the 6MWT, referring mainly to the prognostic stratification in CHF .
31 I.4.2 The six minutes walking test: introduction
This test was initially used for the evaluation of patients with chronical res-piratory diseases, like COPD, or in evaluating stages of resres-piratory insuffi-ciency and, hereafter, began to be used also in cardiology, mostly as a measurement of the functional capacity, but it was also utilized to estimate the efficacy of the therapy, and for prognostic stratification 70. Even though the 6MWT is not able, by itself, to determine the aetiology of the functional limitation and of the dyspnea of a patient, and although it does not deter-mine the peak of maximum oxygen consumption (as, on the other hand, the CPET does), it seems to correlate more, compared to other tests such as the CPET, with daily life activities and quality of life 71 72 .6MWT is a test of simple execution, and does not require expensive instruments or an ad-vanced training by the professionals. It consists in asking the patient to walk the longest possible distance in a time frame of six minutes, usually along a hospital corridor. The patient can slow down, modify and possibly stop his walk at any time, based on his grade of dyspnea of fatigue, and then restart his walk whenever he feels like it 70. The first studies on the use of 6MWT in CHF date back to mid 1980's ; Guyatt72 and Lipkin73 reported that the dis-tance covered during the test can identify the most compromised patients and differentiate them from the less serious cases, based on the NYHA clas-sification.The test displayed also a good correlation to the objective meas-ures of tolerance to exertion, such as exercise duration and the oxygen
up-32 take at the peak of the exercise.Furthermore, patients preferred the 6MWT to the conventional exertion tests on cycle ergometer or treadmill, because such a test seemed to them more similar to daily life activities.
33 I.4.4 Determinants of the 6MWT and use of a reference equation.
The distance walked in the 6MWT is related to different parameters, that should be taken into consideration in the evaluation of the results of this test. Regarding cardiovascular parameters, some studies found that there is just a weak, if any, correlation of the results of the 6MWT with haemodynamic indices (such as left ventricular ejection fraction, pulmonary wedge pres-sure, right atrial prespres-sure, cardiac index and deceleration time ) recorded at rest 74 . Other papers described a correlation of the exercise capacity with indices of right ventricular function like right ventricular ejection fraction 75
25
and mean pulmonary arterial pressure 76; these studies suggest that car-diovascular performance is largely influenced by the impairment of pulmo-nary circulation, and that right ventricular function may be more important than left ventricular function in determining exercise capacity. Several non cardiopulmonary parameters are related to the distance covered at the 6MWT, including anthropometric variables like age, gender, weight and height and also muscular strenght and general health 70.
Consequently, the 6MWT might be considered more as a global perform-ance test rather than a cardiovascular and respiratory test.Therefore, in order to have a more accurate evaluation of the functional capacity of the patient, reference equations that consider these parameters have been proposed 77, and it has been suggested that the results of the test should be expressed not
34 only as an absolute value, but also as a percentage of the predicted value, on the basis of reference equations that take into consideration age, gender , weight and height, estimated by Gibbons et al 78 and Enright77, and sug-gested by the ATS guidelines for the 6MWT71.
I.4.4 Indications for a 6MWT according to ATS guidelines
The American Thoracic Society Guidelines for the 6MWT 71 recommend the use of the 6MWT not only in subjects with lung disease but also in those with heart failure as a onetime measure of functional status and for the evaluation of the effects of therapy and prognostic stratification.
35 I.4.5 The problem of the reproducibility and the safety of the test
The problem of the reproducibility of this test has been investigated by Opasich et al79, who pointed out that the distance walked tend to increase when the test is repeated, and it then remain stable from the second test on-wards. However, the increase in the distance walked during the second test usually does not exceed 10% 72. Encouragement during the test showed to have an effect on the distance walked 80; as such a standardised protocol that involve encouragement at every minute of the test is recommended by ATS guidelines .The 6MWT is considered a safe and highly acceptable test
72 71
, although ATS guidelines indicates as absolute contraindications unsta-ble angina and myocardial infarction during the previous month, and as relative contraindications a resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a diastolic blood pressure of more than 100 mm Hg.
36 I.4.6 The prognostic significance of the 6MWT
Many different studies have investigated whether the distance walked during the walking test is a prognostic indicator in CHF patients.The prognostic predictive value of 6MWT was first reported by Bittner et al 81, who found that the distance walked was an independent predictor of mortality or hospi-talization; in particular mortality was 10.23% in patients who walked less than 350 m in comparison to 2.99% (P<0.01) in patients who walked more than 450 m. The difference between the two groups is even more evident when considering hospitalizations for heart failure (22.16% vs 1.99%). The prognostic negative value of a distance < 300m in patients with mild to moderate heart failure ( NHYA class II and III) was also confirmed by Roul et al 82 ; moreover these authors pointed out that for those who cover a short (less than 300 m) distance, there is a significant correlation between the 6MWT and peak VO2, demonstrating the potential of this simple procedure as a first-line screening test for this subset of patients. Bettencourt et al 83 also enrolled patients with mild to moderate heart failure, and they con-firmed that patients who covered less than 350 m at 6MWT had a worse prognosis; these authors also observed that plasma levels of BNP, ischae-mic aetiology and atrial fibrillation were independently related to prognosis as well.The prognostic significance of the distance walked was also found to be predictive of an adverse outcome in the setting of advanced heart fail-ure, in different papers; Cahalin et al 27 noted, among patients with
ad-37 vanced heart failure being evaluated for heart transplantation, that the walking test was able to predict short term (6 month) mortality or the need for inotropic support, whereas the VO2 peak has been shown to be a better mid-long term prognostic indicator. As previously mentioned, there is a strong relationship between 6MWD and VO2 peak ( as prognostic markers), as Zugk et al 25 found in patients with dilative cardiomyopathy; the authors demostrated that distance walked at 6MWT and pVO2 gave the same prog-nostic information, as the patients who were hospitalized due to worsening heart failure and/or died from cardiovascular causes walked a shorter dis-tance (423+/-104 vs 501+/-95 m, P<0.001) and had a lower peak oxygen up-take (12.7+/-4.0 vs 17.4 + 5.6 ml x min(-1) x kg(-1), P<0.001 ) compared to the clinically stable patients . Moreover they demonstrated that a change in the distance walked in the individual patient does predict a change in pVO2. 6MWT performance was assesed as a prognostic marker comparable to pVO2 also in a recent paper by Forman26 et al, in the setting of ambulatory outpatients with CHF.
38 I.4.7 The 6MWT in the evaluation of the effectiveness of the therapy
The 6MWT has been used in many studies to assess the effect of therapeutic interventions in patients with heart failure, examined in a recent review by Olsson et al 84.The authors examined 47 randomized trials in which distance walked at 6MWT was an outcome end-point of treatment. Overall a signifi-cant increase of exercise performance was found just in 12 of the 47 pla-cebo controlled studies, and there was no improvement in the majority of studies regarding ACE-inhibitors and beta-blockers.Hence, the authors con-cluded that the 6MWT has not been demostrated yet to be a valid test for the identification of effective pharmacological interventions. Nevertheless, it should be noted that most of the patients selected in the trials reviewed by that paper were in NHYA class 2, and in this subset of patients the 6MWT performance shows a high variability . More impressive are the results of investigations in patients with more severe heart failure (NYHA class III– IV), in particular four out of six trials on cardiac resynchronization therapy involving mostly advanced CHF patients, showed a significant improve-ment of distance walked at 6MWT with high concordance with the im-provement of symptoms; this may be related to the fact that in advanced heart failure patients the 6MWT seems to work more as a maximal rather than a sub- maximal test. Indeed the advanced patients are probably exercis-ing near their peak oxygen consumption, as suggested by Faggiano et al 85.
39 To conclude, it can be noted that the 6MWT has proven to be a safe, well acceptable, inexpensive and easy- to -perform way to assess functional ca-pacity and it is able to provide valid prognostic informations, comparable, to some extent , to that provided by the CPET; as a consequence , it might be of great usefulness as a first line screening of the patients with CHF, and, in-tegrated with the informations provided by the values of natriuretic peptides, we espect to obtain a significant prognostic stratification.
40
II Aims of the study
In the present study, we sought to investigate the prognostic value of exercise tolerance as assessed by 6MWT in patients with both CHFrEF and CHFpEF. To gain information in the outcome prediction patients were further characterized according to their BNP values
41
III Matherials and methods
III.1 Study population and clinical assessment
We performed a longitudinal study, evaluating the survival of 616 patients with stable CHF referred to our ambulatory for clinical evaluation and follow-up.The population included patients with stable chronic heart failure due to either ischaemic and non ischaemic aetiology, and both patients with preserved and reduced ejection fraction were enrolled.The preserved ejection fraction was considerd to be > 0.45 at the echocardiography.A complete clinical assessment was performed at each visit, including physical examination, heart rate and blood pressure measurements. An EKG was also recorded. B-type natriuretic peptide (BNP), as well as creatinine levels, serum electrolytes and a complete blood count were measured within 7 days from the date of the follow up and recorded.Plasma BNP was measured according to the chemilluminescent microparticle immunoassay ( ARCHITECT BNP). For each patient clinical data recorded were: age, history and aetiology of HF, NYHA functional class, presence of diabetes, current medications, height, weight, and blood pressure. NYHA class was determined based on clinical history, physical examination, and an understanding of the patient’s activity level which produced symptoms of fatigue or dyspnea. The patients were followed up for a mean period of 60 months for the end point of all-cause mortality;
42 during the follow-up period, the frequency of clinical assessments was decided by the clinician, on individual basis. The study was performed by the University Cardiology of Pisa in collaboration with the Cardiology of Rome Santo Spirito Hospital
III.2 Echocardiography
Comprehensive Doppler echocardiography, including M-mode, two-dimensional echocardiography, and colour and pulsedwave Doppler measurements, was performed in all patients after their initial clinical evaluation with commercially available systems. LV volumes and EF were calculated from apical 2- and 4-chamber views using the modified Simpson’s rule. Maximal left atrial (LA) end-systolic volume was measured from the apical 4-chamber view. Right ventricular systolic function was evaluated by M-mode echocardiography using the tricuspid annular plane systolic excursion (TAPSE). Pulsed wave Doppler mitral flow was analyzed for peak E and peak A velocities, E⁄A ratio, and E wave deceleration time (EDT).
43
III.3 Six minutes walking test
A 6MWT was performed by each patient after the first clinical and echocardiographic examination. Exclusion criteria, according to ATS guidelines, were unstable angina or myocardial infarction during the previous month, and severe gait disturbances evaluated case by case by the clinician. The tests were performed in a flat hospital corridor, and patients were instructed to walk as many meters as they could within six minutes, but not to run or jog during the test. They were also informed to stop or slow down at every moment if they experienced chest pain, intolerable dyspnea, leg cramps, dizziness, diaphoresis, and if the instructor observed a staggering gait or a pale or ashen appearance. Blood pressure was measured at the beginning and at the end,while heart rate and oxygen saturation were continuosly monitored during the test with a pulse oximetry. Patients were also asked to graduate their level of dyspnea and fatigue at baseline and at the end of the test using a modified Borg scale, according to ATS guidelines, from 0 ( complete absence of dyspnea and fatigue) to 10 (very severe / maximal dyspnea and/or fatigue). As no patients with a NHYA class 4 was enrolled, no one was sympotmatic at rest (at baseline). During the test, a standardised encouragement was given at every minute and 15 seconds to the end of the test, also informing the patients about how many minutes were left. At the end of the test the distance walked in meters, blood pressure, oxygen saturation, heart rate and the level of dyspnea and fatigue
44 were recorded. The patients were also asked to assess whether they could walk farther. For each patient it was also determined the % of the predicted distance by means of a reference equation77 :
Men: predicted6MWD =(7.57×height(cm))−(1.76 weight(kg))−(5.02×age)−309 Women:predicted6MWD= (2.11×heightcm)−(2.29×weightkg)−(5.78×age) + 667 Baseline and end-of-the-test characteristics are shown in table 2
III.4 Statistical analysis
Continuous variables are expressed as mean ± standard error of the mean, except variables with a non-Gaussian distribution, which are reported as medians and interquartile ranges (IQR). To assess the prognostic significance of the BNP and 6MWT we first chose a priori 9 initial candidate variables from the database ( 6MWT distance, 6MWT % of predicted , BNP, age, NHYA class, creatinine, LVEF, TAPSE, EDT) on the basis of their proven predictive power of all-cause death from previous studies . For each variable, receiver operating characteristic (ROC) curves were constructed, to assess the accuracy of the variable in predicting prognosis and to determine cut-off points of abnormal values (for continous variables), chosen as the points of the ROC curve showing the optimal balance between sensitivity and specificity with respect to the predicted probability of an outcome event.
45 The strength of association between each candidate variable and long-term mortality was confirmed by means of univariate Cox regression models. Variables more significantly associated with the outcome were then entered into a multivariable Cox regression model to identify the independent predictors of mortality, on the basis of the chi square test.
To assess the specific predictive power of the 6MWT alone, and of the 6MWT combined with BNP, we then analysed survival at 60 months (1800 days) with the Kaplan–Meier method, using the BNP and 6MWT cut-off levels determined previously by the ROC curves.Statistical data were analyzed using the Med Calc and Statview softwares.
46
IV Results
IV.1 Patients characteristics
The population enrolled involved both patients with CHF with reduced ejection fraction (LVEF< 45%) ( 393 patients, 63,8% ) and with CHF with preserved ejection fraction (LVEF > 45%) (221 patients, 36,2%). Mean LVEF was 42%. CHF was of ischaemic aetiology in 214 patients (35%). Most of the patients were in NHYA class 2 (67%) while NHYA class 1 were 12% and NHYA class 3 were 21%, no patients were in NHYA class 4. The median value of BNP plasma levels was 90 pg/mL, interquartile range 60-200 pg/ml. Mean follow up period was 60 months; during the follow up period, 76 deaths occured ( overall mortality rate at 60 months 12%). Baseline patients characteristics are presented in detail in Table 1
47 Age (years) 70±11 Male (%) 68 Heart rate (bpm) 74 ±13 Atrial fibrillation (%) 18 Ischemic Etiology (%) 35 Hypertension (%) 79 Diabetes (%) 25 Echocardiographic Parameters LVEF (%) 42 ±8 EDV (ml) 168±64 ESV (ml) 95±54 EDT (ms) 217 ±107 TAPSE (mm) 19±3.1 Biochemical Parameters Creatinine (mg/dl) 1.25±0.52 BNP (pg/mL) 96 (60-200) Medication Furosemide (%) 77 ACEi/ARB (%) 90 Beta Blockers (%) 76 MRA (%) 50
Table 1. Baseline characteristics. Data are presented as Mean ± standard deviation (SD) or as Median and interquartile ranges (IQR). Abbreviations: LVEF, left ejection fraction; EDV, end-diastolic volume ; ESV, end-systolic volume; EDT, E wave deceleration time; TAPSE, tricuspid annular plane systolic excursion; BNP, B-type natriuretic peptide; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin type 1 receptor blocker; MRA, mineralocorticoid receptor antagonist
48
BASELINE END OF THE TEST
Systolic blood pressure(mmhg) 128 ± 20 135 ±22 Diastolic blood pressure(mmhg) 70±12 72±13 SpO2 % 97 ±2.36 96.6±2.89 Heart rate (bpm) 74 ±14 83 ±17
Symptoms (Borg scale) 0/10 2/10
Distance walked (meters) 335±124 % of the predicted distance 70.5 ± 24.7
Table 2. Baseline and end-of-the –test characteristics. Data are presented as mean ± standard deviation .
49
IV.2 ROC analysis
The results of the ROC analysis for the 6MWT and the BNP are shown in figures 1 and 2. The Receiver Operating characteristics of 9 parameters (6MWT distance, 6MWT % of predicted, BNP, NHYA class, age, creatinine, LVEF, TAPSE and EDT) are illustrated in detail in table 3. For each variable the cut-off level, specificity, sensitivity and the area under the curve are determined.
50 Fig 1. ROC curve of the 6MWT, C.O.= 323 meters, AUC =0,68
51 Table 3. ROC characteristics of 9 variables, C.O= cut off, AUC= Area under the curve.
As shown in table 3, BNP, creatinine and TAPSE were found to be the most accurate parameters in risk prediction. BNP resulted as the most specific variable, whereas age is the most sensitive, although it lacks in specificity. Given the fact that the % of predicted distance showed less accuracy than the 6MWT distance, in the further analyses only this latter was considered.
Cut-off AUC SENSITIVITY SPECIFICITY
6MWT(meters) 323 0.68 71.6 58.1 6MWT (% of predicted) 57 0.62 45.7 77.1 BNP (pg/ml) 330 0.77 56.8 89.2 NHYA class >2 0.62 38.3 81.3 Age (years) 68 0.68 87.7 44.5 Creatinine(mg/dl) 1.26 0.77 76.5 66.4 LVEF 0.45 0.64 65.4 58.5 TAPSE (mm) 18 0.76 74.1 69.3 EDT(ms) 166 0.62 50 75
52
IV.3 Cox regression analysis: predictors of all-cause death
In table 4 are depicted the results of the univariate COX regression analysis for 8 predictors of all-cause death.Chi square test, hazard ratio and the P.value of each variable are determined. All the parameters are expressed as continous variables.
Table 5 shows the multivariate Cox regression analysis for the six variables most significantly associated with the outcome at the univariate analysis, associated with gender (expressed as a nominal variable).
Chi-square H.R. P.value TAPSE 64.04 0.80 <0.0001 BNP 57.20 1 <0.0001 Creatinine 41.30 1.79 <0.0001 6MWT 28.20 0.99 <0.0001 Age 19.80 1.055 <0.0001 NHYA class 14.95 2.16 <0.0001 LVEF 10.57 0.25 <0.0001 EDT 6.25 0.99 =0.0125
Table 4. Univariate COX regression analysis for 8 variables. H.R= hazard ratio.
53
Chi square H.R P.value
TAPSE 22.41 0.85 <0.0001 6MWT 8.56 0.99 =0.0034 BNP 8.07 1.00 =0.0045 Age 7.49 1.04 =0.0062 Gender 5.02 0.53 =0.250 Creatinine 1.65 1.20 =0.1985 NHYA class 1.02 1.26 =0.3125
Table 5. Multivariate COX analysis for 6 variables
As shown in table 4 and 5, all of the 8 variables were significant univariate predictors of all-cause mortality at the univariate Cox regression analysis. Among them, four ( TAPSE, BNP, 6MWT and age) remained statistically significant in the multiple Cox regression analysis .The most signficant variable was the TAPSE, but the BNP and the 6MWT showed a good performance as well, as independent predictors of all-cause mortality.
54
IV.4 Kaplan Meier survival curves
In figure 3 are illustrated the Kaplan–Meier survival curves for patients stratified on the basis of the 6MWT. Patients were categorized into two groups on the basis of the cut-off level of the 6MWT (323 meters ) previously determined at the ROC analysis.The group of patients with 6MWT <323 meters (281 patients) had a 64% survival rate at 60 months, whereas the group with 6MWT > 323 meters (335 patients) had a 87% survival rate at 60 months ( Chi square log-rank test = 24.4, P < 0.0001). Then the patients were further categorized into four groups on the basis of the 6MWT (cut-off: 323 meters) and BNP (cut-off: 330pg/ml) combined.The figure 4 shows the Kaplan Meier survival curves for patients stratified according to these two variables: at 60 months the group with BNP >330 pg/ml and 6MWT<323 meters (61 patients) had a 31% survival rate, the group with BNP >330 pg/ml and a 6MWT >323 meters (42 patients) had a 68% survival rate , the group with BNP <330 pg/ml and 6MWT <323 meters (220 patients) had a 82% survival rate and the group with BNP<330 pg/ml e 6MWT >323 meters (293 patients) had a 92 % survival rate (Chi-square logrank test = 113, P<0.0001).
55
Fig 3. Kaplan Meier survival curve on the basis of the 6MWT
56
V Discussion
The present study demonstrates, in a large cohort, that the integration of the BNP values with the results of a 6MWT can provide significative information about the risk of death in CHF patients. The 6MWT performance proved to have a significant prognostic power at univariate Cox analysis, and most importantly, was found to be an independent predictor of mortality at multivariate Cox analysis. With the Kaplan Meier model, patients who covered a distance below a cut- off of 323 meters showed a significant decrease in the survival rate, compared to the group of patients above that threshold. Of note, the cut-off level found to be predictive of poor prognosis is similar to that found in previous studies81-83. However, we found that adding the BNP values to the 6MWT results in a much more accurate risk stratification. Surely, the intrinsic limitations of the 6MWT can reduce its predictive strength; the walking performance is, in fact, related to several parameters, as discussed previously, such as morphometric variables like height and weight, and it is also affected by osteoarticular diseases, like coxophemoral arthrosis. Furthermore, our cohort consisted mainly of mild to moderate CHF patients (NHYA classes 1-2), and in this subset of patients the 6MWT could be considered more as a submaximal, rather than a maximal test. The 6MWT acts as a maximal test, comparable to the CPET, only in advanced CHF patients, among which
57 however the CPET provides more specific information, and seems to be irreplaceble, especially in the evaluation of an eventual cardiac transplantation. Nevertheless, the 6MWT demonstrated to be an independent predictor of poor outcome at the COX multivariate analysis, while the NHYA class, the most used parameter of functional capacity in the clinical practice, showed no independent predictive value, if integrated with other variables. Moreover, even at the univariate analysis, the 6MWT showed to be a better predictor of all- cause mortality compared to the NHYA class. This finding enforces the conviction that an objective measurement of the functional capacity is needed in order to provide prognostic information, and the 6MWT seems to be a reliable way to assess functional capacity. As already discussed, several authors have ascertained how the 6MWT is a well acceptable and tolerated test, and how it seems to be closely related to the self reported quality of life. Thus, we can assume that even if it is not able, by itself, to establish a very precise prognostic stratification, it is still a useful test for a standardized evaluation of the functional limitation of the CHF patients, and might be used in the clinical practice as a first line screening of the exercise capacity and the prognosis of the patients. BNP levels were found to be one of the most significant predictors of all-cause death both at univariate and multivariate analysis. Furthermore, adding the values of the BNP to the 6MWT results in a significant discrimination of the patients at high risk of death, with a poor
58 survival rate (around 31% at 60 months) in the subset of patients with a reduced walking performance and elevated BNP values .
Consequently, the integrated approach with these two parameters has demonstrated to be a reliable and inexpensive way to assess the prognosis in CHF patients, and is able to predict events with more accuracy than the simple clinical evaluation. In fact,with the current state-of-art therapy, most of the ambulatory CHF patients (NHYA classes 1 and 2) have few symptoms, particulary at rest; moreover, only a few signs can be found with the physical examination. As such, the proposed approach might be of great value, especially for the general practitioner and for the internal medicine specialist, as a first line screening able to identify those suitable to be referred to the cardiology specialists for a more accurate evaluation.The strategy proposed in the present study can be easily and efficiently used in the clinical setting to predict long-term mortality and, most importantly, it shows independent predictive power over historical and strong clinical predictors of adverse outcome in CHF such as age, NYHA class and chronic kidney disease. Of note, the two parameters considered can represent different but complementary aspects of the CHF syndrome: it is in fact well known that CHF is a complex syndrome that does not involve solely the heart, but significant alterations in several tissues and organs has been found, mainly as a consequence of the neurohormonal activation and of the haemodynamic changes. For example, as previosuly cited, the skeletal
59 muscle shows severe structural and functional abnormalities in CHF, with an excess of catabolism that terminates in the condition of cardiac cachexia, in the advanced stages of the disease. The 6MWT, being a more a global performance test rather than just a cardiovascular perfomance test, is probably able to investigate the above mentioned alterations in the skeletal muscle, and in general the "syndromic" aspects of CHF. On the other side, the values of the BNP are more closely related to central haemodynamic parameters and indices of cardiac function. Consequently, these two parameters taken together might represent a simple way of assessing different important features of the disease, with the 6MWT more associated with the general impairment of all the organism and the BNP more associated with elevated filling pressures and excess of neurohormal activation.
Nevertheless, the prognostic evaluation, cannot rely only on this approach, but it is necessary to perform an adeguate clinical assessment, considering also the most important comorbidities, such as renal insufficency, and echocardiographic parameters. Of note, in our study the right ventricular systolic function, evaluated with the tricuspid annular plane systolic excursion (TAPSE) , was the most powerful predictor of death both at univariate and multivariate analysis, whereas LVEF, a parameter more frequently considered in previous studies, was not an independent predictor at multivariate analysis and showed only a modest predictive power at the
60 univariate analysis. This can partially be explained by the fact that our population included both CHF patients with reduced LVEF and patients with preserved LVEF; it is possible that, considering only patients with a reduction of the LVEF, this latter remains a reliable prognostic marker. However, our findings are similar to those from a recent study 35 that tries to establish an echocardiographic risk predction score, evaluating the predictive power of several echocardiographic parameters in a population of CHF with reduced EF patients. Moreover, another recent paper 86 by Dini and colleagues has assessed the prognostic relevance of the right ventricular dysfunction, and suggested it as one of the possible mechanisms that links CHF to chronic kidney disease.
Accurate determination of risk has become an important step in the management of patients with CHF. Risk stratification is important in making appropriate decisions for selection of site and level of care, and need for therapeutic interventions. In particular identifying the patients with more risk might allow the clinician to establish a personalized follow up, based on the integration of all the above mentioned parameters; in this way the patients at high risk would be followed up more closely, in order to promptly identify the signs of CHF decompensation and to perform the appropriate therapeutic interventions.
The concept of a CHF therapy guided by the results of a specific parameter has already been investigated in several studies, in particular regarding the
