Prognostic value of combining echocardiography and natriuretic peptide levels in patients with heart failure

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Heart failure (HF) is still a global public health issue, despite the enormous progress made in its diagnosis and treatment. More often than not, acute or chronic decompensated HF leads to hospitalization and presents a dismal prognosis. Evidently,
  MANAGEMENT OF HEART FAILURE (T. MEYER, SECTION EDITOR) Prognostic Value of Combining Echocardiographyand Natriuretic Peptide Levels in Patients with Heart Failure Wei-Hsian Yin  &  Jaw-Wen Chen  &  Shing-Jong Lin Published online: 21 February 2012 # Springer Science+Business Media, LLC 2012 Abstract  Heart failure (HF) is still a global public healthissue, despite the enormous progress made in its diagnosisand treatment. More often than not, acute or chronic decom- pensated HF leads to hospitalization and presents a dismal prognosis. Evidently, clinical symptoms alone are not reli-able enough guidance for the HF treatment; therefore, parameters able to identify adverse prognoses are valuablein tailoring treatment regimens for individual patients.Echocardiography and natriuretic peptides (NPs) have dem-onstrated their capacities in giving independent diagnosticand prognostic information regarding patients with HF.Although abnormalities either of an echocardiographic indexof left ventricular function or of an NP denote an increasedrisk of mortality or HF, the highest risk comes from abnor-malities of both left ventricular function and NP levels. In thisreview, we survey the most recent publications exploring theutility of NP levels and echocardiographic indices integration,claimed to offer powerful incremental prognostication in patients with established HF. Keywords  Heartfailure.Acuteheartfailure.Chronic heart failure.Systolicheartfailure.Diastolicheartfailure.Left ventricularfillingpressure.Biomarkers.Multi-marker strategy. Natriuretic peptides.B-typenatriureticpeptide. N-terminalpro-B-typenatriureticpeptide.Echocardiography.TissueDopplerimaging.MitralE/Ea .Prognosis.Clinicaloutcomes.Predictivevalue. Neurohormonalactivation.Ventriculardysfunction.Hemodynamic.Riskstratification Introduction Heart failure (HF) remains a serious public health concernworldwide, despite the enormous progress already made inits diagnosis and treatment. As far as Westerners aged over 65 years are concerned, the leading causes of hospitalizationare acute and chronic decompensated HF. Consequently, theguidelines on this subject have been recently updated [1, 2]. Echocardiography is the most useful diagnostic instru-ment in the evaluation of patients with HF [1  –  3]. Echocar-diographic indices of cardiac structure and function are alsoreliable predictors of mortality in patients with HF [3, 4]. Furthermore, in recent years, echocardiographic techniquesapplicable to HF patients have progressed rapidly. Newtechniques such as tissue Doppler echocardiography (TDI)have been developed to image hemodynamics and myocar-dial mechanics, which provide clinicians with more accuratemeasurements for diagnostic and prognostic purposes [5  –  7].Although conventional Doppler indices and TDI parameterscorrelate with functional status in patients with a significant left ventricular (LV) dysfunction or advanced HF, the com- bined assessmentof transmitral blood flow velocities by spec-tral Doppler echocardiography and mitral annular velocities by TDI (mitral E/Ea), which probably reflects high LV filling W.-H. Yin ( * )Division of Cardiology, Heart Center, Cheng-HsinGeneral Hospital; Faculty of Medicine, School of Medicine, National Yang-Ming University, No. 45, Cheng-Hsin Street, Pei-Tou, Taipei 112,Taiwan, Republic of China e-mail: Yine-mail: J.-W. Chen :  S.-J. LinDepartment of Medical Research and Education, Taipei VeteransGeneral Hospital; Institute of Pharmacology, School of Medicine, National Yang-Ming University, No. 201, Section 2, Shih-Pai Road, Pei-Tou, Taipei 112,Taiwan, Republic of China Curr Heart Fail Rep (2012) 9:148  –  153DOI 10.1007/s11897-012-0082-z   pressure, has been proven to be one of the best diagnostic and prognostic echocardiographic parameters [3  –  7].Other new plasma-based biomarkers have, on the other hand, proved to be powerful risk predictors in the patientssuffering from HF [8, 9]. Among them, natriuretic peptides (NPs), especially the B-type natriuretic peptide (BNP) andits amino-terminal cleavage fragment N-terminal pro-B-typenatriuretic peptide (NT-proBNP), are easily available androutinely accessible to clinicians [8  –  11]. These biomarkers,either induced by pressure or volume overload, are closelyassociated with the presence and severity of abnormalities incardiovascular structure and function [8  –  11]. Moreover, in patients with both acute and chronic HF, NP levels areamong the strongest independent predictors of hazard, andtheir measurement is useful for prognostication across theentire spectrum of HF disease severity [10  –  14]. In patientswith both acute and chronic HF, repeated determinations of  NP levels appear to convey additional prognostic values for relevant adverse outcomes, including death or HF hospital-ization [10  –  14]. Meanwhile, multimarker strategy measur-ing the levels of multiple biomarkers simultaneously,including a NP, may allow rapid risk stratification to identify patients with advanced HF at a high risk of adverse out-comes [15].Although both BNP and NT-proBNP are promisingmarkers in HF and both assays are reliable, giving goodanalytical performances, their diagnostic cut-off values varyand are population-dependent [11, 16, 17]. The slightly wider detection range and the more stable structure of  NT-proBNP than those of the BNP assay suggest that  NT-proBNP could play an additional role in the evaluationof patients with LV systolic dysfunction [16, 17], although it  may be advisable to keep in mind confounding factors, suchas renal function or obesity, while prognostically evaluating patients with the use of NT-proBNP measurements [13, 14]. On the other hand, in survivors of acute decompensated HF,BNP levels decline more rapidly than NT-proBNP levelsand, thus, seem to allow earlier assessment of treatment efficacy [17].Given the fact that echocardiography and the NPs pro-vide powerful assessments of cardiac structure and functionand clinical status across the spectrum of cardiac disease,and that echocardiographic indices and NP levels yieldimportant prognostic information in patients with acute andchronicstableHFindependentofother clinicalvariables,bothof them are variables helpful in the management of patientswith HF. Furthermore, significant correlations between circu-lating NP levels and some echocardiographic parametersreflecting left and right ventricular (RV) functions have beendemonstrated when most of the LV TDI-derived indices werenot significantly correlated to NP values [18 • , 19]. Therefore,the NPs may provide additive predictive power to echocardi-ography in patients with HF, and vice versa. In this article, wediscuss the clinical use of echocardiography in combinationwith NPs in HF, focusing on their prognostic values. Rationale of Combining Echocardiography and NPMeasurements in Patients with HF There are four reasons to use echocardiography and NPs incombination for risk stratification in patients with HF.First, echocardiographic indices such as mitral E/Ea andBNP have been correlated with LV filling pressures and proved their high sensitivity for pulmonary capillary wedge pressure (PCWP) greater than 15 mm Hg, yet mitral E/Ea has a better correlation than BNP with LV filling pressureand, thus, appears more precise and accurate in patients withcardiac diseases [20, 21]. However, mitral E/Ea has a sig- nificant   ” gray zone ”  and is not well validated in non-sinusrhythm or mitral valve disease, whereas NP measurementsmay be useful for the assessment of LV filling pressures in patients with inconclusive tissue Doppler indices [22 • ].Second, NPs are proteins released by the ventricles in the presence of myocytic stretch, and the NP levels reflect a compilation of systolic and diastolic as well as RV andvalvular functions [10]. Therefore, even though the NPlevels correlate with LV filling pressure, they may provideadditive clinical information independently to other cardiacmorphological abnormalities. In fact, NPs already have beenobserved to predict long-term mortality and readmission for HF independent of echocardiographic parameters [23  –  26].Third, NPs are significantly affected by age, sex, renalfunction, and obesity, so they may yield intraindividualvariations over time. That is, NPs are characterized withhigh sensitivity but low specificity for the detection of elevated LV filling pressures [10, 21, 26, 27], whereas echocardiography may improve the accuracy of HF diagno-sis and prognostication in the setting of intermediate BNP or  NT-proBNP levels [21].Fourth, the treatment for patients with HF can causechanges of mitral E/Ea and NP levels. While LV filling pressures were being manipulated, the relationships betweenmitral E/Ea and PCWP became highly variable, which sug-gests that mitral E/Ea failed to track changes in LV filling pressures adequately [28 • , 29 • , 30 • ]. Hence, although both NP levels and mitral E/Ea are variables helpful in the man-agement of patients with HF, they may not be interchange-able indices and can respond differently during the treatment [18 • , 21, 28 • , 29 • , 30 • ].If the respective strengths and limitations of NPs andmitral E/Ea are taken into account, algorithms combiningthem can be used to more accurately estimate LV filling pressures in patients presenting with dyspnea was recom-mended [1, 2, 21]. Moreover, echocardiographic indices and  NP levels applied in combination may provide clinicians Curr Heart Fail Rep (2012) 9:148  –  153 149  with additional important prognostic information in patientswith HF independent of other clinical variables. Combining Echocardiography and NP Measurementsin Patients with Chronic Stable HF Evidently, the integrated use of echocardiography and NPsin the diagnosis and management of HF is preferred for a combined assessment of NPs, and echocardiography presents more full stratification of risk across all stages of chronic HF [21, 31  –  35, 36 •• ].In patients with chronic systolic HF stabilized by medicaltreatment, the combination of echocardiographic indices and NT-proBNP has been noted to supply independent andincremental contributions to prognostic stratification [31,32]. In New York Heart Association (NYHA) class I andII patients, NT-proBNP and mitral E/Ea ratio are also incre-mental for risk stratification [33]. Moreover, NT-proBNP or BNP may guide more effective use of echocardiography inscreening and risk stratification for stage A/B HF patients[34, 35]. In addition, the integration of both tests may identify patients with valvular disease at the greatest risk for progression and guide decision making timely to anintervention [36 •• ].Other echocardiographic indices of cardiac structure andfunction independent of NP levels as strong predictors of mortality in patients with HF include LV size and function,Doppler LV diastolic variables, and left and right atrial sizes[19, 31, 33, 34, 36 •• ]. Combining Echocardiography and NP Measurementsin Patients with Acute HF Acute HF is the most common diagnosis at discharge in patients aged over65 years. It carries a dismal prognosis, withhigh in-hospital and a very high postdischarge mortality rates,aswellasrehospitalizationrates[37,38].Advancesinthecare of patients with acute HF resulted in a shorter period of hospitalization, which subsequently reduced the risk of hospital-associated adverse events. However, shortening thetime that the patients spend in the hospital may lead to other adverse events during the earlier period of discharge [39, 40]. In terms of the treatment of patients with acute HF, symptomsalone are clearly not a reliable guide because many patientswere discharged on account of their feeling much improved but the outcomes have been far from optimal. Thus, parame-ters able to identify adverse prognoses can be very valuable intailoring treatment regimens for individual patients [37, 38]. In the management of patients with acute HF, the estima-tion of LV filling pressure remains a critical component.Although right heart catheterization remains the golden rule,several noninvasive parameters, including clinical assess-ment, BNP, and echocardiography, have been used to ap- proximate LV filling pressure. Goonewardena et al. [41]sought to use a combination of these measures to predict noninvasively the LV filling pressure in patients with acuteHF and referred for right heart catheterization. They foundthat all parameters performed well in determining PCWP15mmHgorgreater,withjugularvenouspressureperformingtheworst(areaunderthereceiver-operatorcharacteristiccurve[AUC] 0.74), and maximum inferior vena cava diameter andmitralE/Eadetectedbyechocardiographyperformingthebest (AUC 0.89). Jugular venous pressure in combination withechocardiography-derived parameters and BNP performed better than any single one of the other individual tests (AUC0.97 for combination of all 3) [41].In an  “ all-comers ”  population with acute dyspnea under-going echocardiography, NPs correlate strongly with the pres-ence of cardiac structural abnormalities [42]. Dokainish [21] also reported that mitral E/Ea and NPs are valuable aids indiagnosing HF in patients with dyspnea. In general, E/Ea ismore precise than NPs for elevated LV filling pressures;however, NPs have a high negative predictive value for excluding HF. Because both the E/Ea and NPs demonstratesignificant limitations, an algorithm combining NP, the mitralE/Ea, and left atrial volume indexed to body surface area isrecommended to estimate LV filling pressures in patients withacute HF [21].In patients with acute HF, NPs are also powerfully prog-nostic for adverse outcomes, including death [43  –  47]. How-ever, as mentioned, the in-hospital treatment for patientswith acute HF can cause changes of NP levels. WhileBNP levels obtained on admission provide independent  prognostic information of in-hospital mortality [44], BNPlevels during and at the completion of hospitalization (pre-discharge) may reflect adequacy of treatment and are corre-lated to functional class and prognosis [24, 45  –  47]. Perhapsthe addition of pre-discharge BNP levels to a clinical/instru-mental decisional score for discharge decision makes possi- ble the detection of high-risk patients who need a reinforcedtreatment or follow-up [45]. In another study, Bettencourt and Januzzi [13] reported that both presentation and post-treatment NT-proBNP concentrations are valuable for prog-nostication of recurrent HF hospitalization or death; none-theless, the percentage changed in NT-proBNP since thetreatment for acute HF may be a more effective means for risk stratification [13].Recently, researchers have also studied the importance of  pre-discharge BNP alone and in combination with measuresof diastolic dysfunction, including but not limited to mitralE/Ea. Ho et al. [48 •• ] reported that simultaneous pre-discharge assessment of NT-proBNP and mitral E/Ea pro-vided complementary information and, thus, enable clini-cians to stratify risk more effectively for the hospitalized 150 Curr Heart Fail Rep (2012) 9:148  –  153   patients with acute HF. Their findings reinforce the need tocombine the heart hemodynamic variable mitral E/Ea ratioand plasma-based neurohormonal biomarker NT-proBNPwhen clinicians attempt to define the individual risk of hospitalized patients with acute HF [48 •• ]. Those studiesof patients hospitalized for HF that found that a pre-discharge  “ restrictive ”  Doppler pattern was associated withthe highest BNP at discharge and that pre-discharge BNPand a   “ restrictive ”  Doppler pattern or TDI-derived E/Ea together were stronger and amplified predictors of cardiacmortality or rehospitalization for HF [20, 21, 24, 49  –  51]. Inaddition, RV dysfunction adversely affects prognosis in patients with chronic HF due to LV dysfunction, so RVTDI indices combined with increased plasma BNP alsocan additively predict adverse cardiac outcomes in advancedHF due to LV systolic dysfunction [52].The role of echocardiography and NPs in the prognostica-tion for patients with poor LV function since an acute myocar-dial infarction (MI) is well established [53]; also, it is wellknown that most patients who survive an acute MI have preserved or only slightly impaired LV systolic function [54].In post-MI patients with preserved LV function (LV ejectionfraction  ≥ 40%), the baseline NT-proatrial natriuretic peptide, but not echocardiographic LV volumes, predicted adversecardiac events [55]. In a more recent study, Kruszewski et al.[56 • ] reported that both an elevated mitral E/Ea and higher BNP levels were associated with an increased risk of anadverse event. Among those patients whose BNP levels werehigher than the median or reached the upper quartile, a mitralE/Eagreaterthan15identifiedasubgroupatthegreatestriskof mortality, suggesting that the E/Ea ratio and BNP levels playimportant and complementary roles in the risk stratification of  patients after acute MI. Combining Echocardiography and NP Measurementsin Patients with Diastolic HF Abnormalities in diastolic function are common in HF, contrib-ute primarily to signs and symptoms of HF, and are oftenindependent of systolic function [57]. Doppler echocardiogra- phy has been one of the most useful clinical tools for theassessment of LV diastolic function; however, this technique isoften limited by the fact that mitral flow is dependent onmultiple factors that may have confounding effects, such asheartrate,preload,afterload,contractility,valvularregurgitation,andsoforth[58].Theseinherentlimitationssuggesttheneedfor supplementary measures of diastolic dysfunction. Becauseavailable data suggest that NPs partially respond to ventricular  pressure, NP levels may predict diastolic abnormalities in patients with HF and preserved systolic function [57  –  59, 60 •• ].Previous reports have already demonstrated that a rapidassay for BNP or NT-proBNP can reliably detect the presence of diastolic abnormalities on echocardiography[59, 60 •• ]. In HF patients with normal or preserved systolicfunction, elevated BNP levels and diastolic filling abnor-malities may reinforce the diagnosis of diastolic dysfunction[61]. Moreover, although BNP levels do not correlate wellwith mitral E/Ea across the full spectrum of values, thecombination of BNP levels along with mitral E/Ea fromTDI is considered a better predictor of elevated LV filling pressure in patients with suspected diastolic dysfunction, aswell as elderly patients with permanent, nonvalvular atrialfibrillation and diastolic HF [21, 62, 63]. Furthermore, BNP can be useful in prognostication in patients with symptomatic and asymptomatic diastolic dys-function. In an  “ all-comers ”  population with acute dyspnea undergoing echocardiography, NPs identify those with pre-served LVejection fraction at the highest risk for death [42].On-admission and pre-discharge BNP levels in patients withdecompensated diastolic HF have been prognostic with re-spect to in-hospital mortality, short-term mortality, and hospi-tal readmission.Moreover, the combination withother values,including echocardiographic indices and cardiovascular risk factors, can augment the sensitivity and precision of BNP inrisk stratification in patients with diastolic HF [64]. Conclusions The integrated use of echocardiography and circulating NPlevels proffers powerful incremental assessment of cardiacfunction and clinical status in patients with HF. Combinedassessment of NPs and echocardiography also providesincremental power in risk stratification across all stages of HF, be it acute or chronic or systolic or diastolic. Disclosures  No potential conflicts of interest relevant to this articlewere reported. References Papers of particular interest, published recently, have beenhighlighted as: •  Of importance ••  Of major importance 1. ESC guidelines for the diagnosis and treatment of acute and chronicheart failure. The Task Force for the diagnosis and treatment of acuteandchronicheartfailure2008oftheEuropeanSocietyofCardiology.Developed in collaboration with the Heart Failure Association of theESC (HFA) and endorsed by the European Society of Intensive CareMedicine (ESICM). Eur J Heart Fail. 2008;10:933  –  89.2. 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Clin Chem.2004;50:2052  –  8.28.  •  Bhella PS, Pacini EL, Prasad A, et al.: Echocardiographic indicesdo not reliably track changes in left-sided filling pressure inhealthy subjects or patients with heart failure with preserved ejec-tion fraction. Circ Cardiovasc Imaging 2011;4;482  –  9.  This study showed that while LV filling pressures were being manipulated, therelationships between mitral E/Ea and pulmonary capillary wedge pressure became highly variable, and which suggests that mitral  E/Ea failed to track adequately changes in LV filling pressures. 29.  •  Wasywich CA, Whalley GA, Walsh HA, et al.: The relationship between BNP and E/Ea in patients hospitalized with acute heart failure. 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