NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation

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1 NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation Srikornruth Panyaratanakul 1, Tanarat Choon-ngarm 2, Wilai Puavilai 2, Saowaluk Prompongsa 2, Donpichit Laorakpongse 2, Sutham Sutheerapatranont 2, Anan Kriangkrichoke 2. 1 Fellow Cardiology Department, Rajavithi Hospital, Bangkok Thailand 2 Professor Cardiology Department, Rajavithi Hospital, Bangkok Thailand Abstract Objectives: This study will determine plasma NT-proBNP levels as a marker of left ventricle (LV) dysfunction in Asymptomatic Chronic Mitral Regurgitation (MR) patients. Background: It is generally accepted that patients with chronic MR that are asymptomatic with normal LV function do not require surgery. However, it is the definition of normal LV function in this condition that is problematic. It is possible that with information obtained from echocardiography that natriuretic peptide testing in patients with MR will clarify this problem. Methods: Between , patients who had at least moderate chronic asymptomatic MR from the Cardiology Department at Rajavithi Hospital underwent transthoracic echocardiography and had blood collected for measurements of NT-proBNP levels. Results: In the patients that were studied there were 15 males (53.6%) and 13 females(46.4%)with a mean age of 45 years old.the etiology of isolated chronic MR was rheumatic in 5 patients (17.9%), mitral valve prolapse in 16 patients (57.1%), leaflet failure in 6 patients (21.4%) and dilated LV in 1 patient (3.6%). 27 patients (96.4%) were classified as Functional class I and 1 patient (3.6%) as Functional class II. The EKG identified basic rhythm in 25 patients (89.3%) and atrial fibrillation in 3 patients (10.7%). The mean ejection fraction (EF) was 68.5%. Mean LVDD, LVSD, ESV and EDV were as follows mm, mm, mm, cc respectively. From the results of the echocardiography 17 patients (60.7%) were treated medically and 11 patients (39.3%) were scheduled for surgery. The Mean level of NT-proBNP is720pg/ml. NT-proBNP levels increased above normal in 89% of the patients. From the ROC data NT-proBNP levels at 1217 pg/ml in MR patients had the best sensitivity and specificity for determining LVSD as well as deciding whether to operate or not. Conclusions: There was a correlation between BNP concentrations and routine echocardiographic indices of LV function in this condition. Patients with chronic MR with NT-proBNP > 1217 pg/m probably need surgery but a lower elevation in NT-proBNP levels may also be significant. NT-proBNP levels may be a useful marker in followingup patients with asymptomatic MR. Thai heart J 2007; 20 : E-Journal : Introduction Deciding when to operate on a patient with chronic mitral regurgitation (MR) is a notoriously difficult problem. It is generally accepted that Correspondence to: Srikornruth Panyaratanakul Department, Rajavithi Hospital, Bangkok 10700, Thailand. address: kaolad@yahoo.com asymptomatic patients with normal left ventricular (LV) function do not require surgery (1). However, it is the definition of normal LV function in this condition that is problematic. The favorable loading conditions mean that current imaging modalities are not good enough at detecting early LV dysfunction and symptoms are often absent until late in the

2 NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation 69 disease course. Thus, many patients are referred for corrective surgery with irreversible LV damage. Echocardiography is the standard method used to evaluate the severity and cause of MR, and to assess LV systolic function (2). However, it may be difficult to obtain an accurate quantitative assessment of the severity of regurgitation (3-4). Quantitative estimates of the severity based on measurements of the regurgitant fraction and the regurgitant orifice area (5) as well as color Doppler are technically demanding. Left ventricular function may also be difficult to evaluate in patients with severe MR because the ejection fraction (EF) can be maintained in the presence of LV dysfunction (6). The American College of Cardiology and American Heart Association recommend surgery for severe MR if symptoms occur or there is evidence of asymptomatic LV dysfunction whichis defined as an LV end systolic dimension of >45 mm or an EF of <60% (7). However, difficulties in detecting early LV dysfunction, accurately assessing the severity of regurgitation, or recognizing early cardiac symptoms can make it difficult to determine the optimal timing of mitral valve surgery (8). Several studies confirm the high incidence of postoperative LV dysfunction and poor long-term prognosis in this group of patients (9-12). For example, Enriquez-Sarano et al (12). reported that LV dysfunction following apparently successful mitral surgery occurred in 41% of 266 patients, and that the eight-year survival rate in this group was only 38%. Thiscompared to 69% in those with normal postoperative LV function. The argument for earlier intervention in the prevention of LV dysfunction is, therefore, a persuasive one, but needs to be balanced against the risks of cardiac surgery and the complications of prosthetic valve implantation. Advances in valve repair have undoubtedly reduced these risks and do improve long-term survival (13). Unfortunately, valve repair is not always possible or predictable and decisions concerning the timing of surgical intervention still depend critically on preoperative assessment of LV function. It is possible that natriuretic peptide testing in patients with MR will add to the information obtained from echocardiography, but to date there are only limited published data. Mitral-Valve Regurgitation is common, and its prevalence increases with age. The management of MR and indications for surgery are controversial. Previous outcome studies showed that patients with organic MR who have symptoms or a reduced EF are at high risk, thus warranting mitral surgery. Conversely, the clinical outcome among patients with asymptomatic MR is poorly defined, and criteria defining high-risk subgroups are uncertain. Such subgroups are important to identify because technical improvements in surgery with decreased operative mortality and increased repair rates allow the restoration of a patients life expectancy. Thus, surgery may be warranted in high-risk patients with asymptomatic MR under medical management. Brain Natriuretic Peptide (BNP) is a cardiac neurohormone identified from porcine brain tissue in 1988 (14). However in humans it is secreted primarily from the ventricular myocardium and from the cardiac ventricles as a response to ventricular volume expansion and pressure overload. BNP levels are elevated in patients with symptomatic LV dysfunction and correlate with The New York Heart Association (NYHA) class as well as with prognosis. Plasma levels are low in the normal population but are elevated in a wide range of cardiac diseases characterized by ventricular dysfunction. In this study plasma BNP concentrations were measured in patients with chronic MR in order to determine whether these could be used as a marker for early LV dysfunction. However, the utility of plasma BNP as a screening test has been limited by the same standard assay issues common to other hormones or cytokines also elevated in heart failure. BNP is used to detect LV dysfunction in patients with chronic MR according to ACC/AHA criteria. It is also used to manage asymptomatic chronic MR in patients. The Differences between BNP and NT-proBNP If the LV function is abnormal, then N- terminal pro-brain natriuretic peptide (NT-proBNP) is secreted and cleaved immediately into NT-proBNP and BNP. BNP is destroyed by the endopeptidase enzyme. Therefore, it is metabolized faster in fat than thin subjects. NT-proBNP is also excreted in constant form by the kidney and also has a longer half-life.

3 70 Srikornruth Panyaratanakul, Tanarat Choon-ngarm, Wilai Puavilai, Saowaluk Prompongsa, Donpichit Laorakpongse, Sutham Sutheerapatranont, Anan Kriangkrichoke. NT-proBNP is a good indicator to identify abnormal left ventricle function and thus more suitable than BNP. Moreover, a sample of NT-proBNP is very easy to measure and obtain since there are automatic tools that are highly accurate and yield precise results (15). Cardiovascular disease is placing an increasing burden on society (16) but may be asymptomatic or misdiagnosed once symptomatic. Accordingly, to reduce this, authors have proposed establishing cardiovascular screening programs (17-18). Natriuretic peptides, a family of peptide hormones released into the circulation in response to increased myocardial stretch, have been proposed as potential biomarkers of cardiovascular disease once they are validated (17-18). Plasma levels of BNP and its co-released peptide NT-proBNP both increase in a variety of cardiovascular conditions (19), although their full screening characteristics are yet to be firmly established (20). Furthermore, unlike BNP, NTproBNP cut-off values have not been established in clinical studies, which is an essential pre-requisite for screening programs. According to The American Society of Transthoracic Echocardiography, the VC width for moderate MR is cm and severe MR is >= 0.70 cm. Severity of MR by jet area is 20-40% of LA area for moderate MR and > 40% of LA area for severe MR. If EROA is cm 2, the MR is moderate and if EROA > 0.4, the MR is classified as severe. All patients had a transthoracic echocardiographic performed by one operator and 3 ml of venous blood collected for the analysis of plasma NT-proBNP. Plasma??? NT-proBNP levels were measured on the Elecsys 2010 system (Roche Diagnostics, Lewes, UK). This assay is an electrochemical sandwich immunoassay using two polyclonal antibodies directed at the NT-proBNP molecule. Intra-assay and inter-assay variabilities were % and %, respectively. Statistical Analysis A Students t??? test was used to compare continuous variables between groups. The Pearson Materials and Methods This study was approved by the Ethical Committee. Informed consent was obtained from all subjects before participation. Between , patients who had at least moderate chronic asymptomatic MR from the Cardiology Department at Rajavithi Hospital underwent transthoracic echocardiographic and blood level measurements of NT-proBNP. Inclusion criteria were asymptomatic and chronic MR with moderate to severe severity. Exclusion criteria were symptomatic patients, other valve diseases with moderate severity, recent congestive heart failure and renal failure. Two-dimensional echocardiography was performed with a Toshiba using second harmonic imaging. Left ventricular ejection fraction (LVEF) was calculated. LVDD, LVSD, EDV, ESV were measured twice and the results were averaged. The severity of MR was determined by three methods; VC, EROA and Jet area. At least two out of three methods had to show at least moderate severity to qualify for this study. Table 1. Baseline Characteristics Variables Sex Age (yr) Functional Class EKG Etiology Male Female Over 60 I II Sinus AF RHD MVP Fail Leaflet LV Dilate Frequency Percentage

4 NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation 71 correlation coefficient was used to assess the association between the Ln levels??of natriuretic peptide and echocardiographic variables. The areas under the receiver-operator characteristic (ROC) curves were used to evaluate the diagnostic performance of NT-proBNP and echocardiographic measurements. Results We collected a total of patients; 15 male (53.6%) and 13 female (46.4%) with a mean age of 45 years old. The etiology of isolated chronic MR was rheumatic in 5 patients (17.9%), mitral valve prolapse in 16 patients (57.1%), leaflet failure in 6 patients (21.4%) and LV dilated in 1 patient (3.6%). There were 27 patients (96.4%) in Functional class I and 1 patient (3.6%) in Functional class II. The EKG identified sinus rhythm in 25 patients (89.3%) and atrial fibrillation in 3 patients (10.7%) (Table I). The mean EF was 68.5%. Mean LVDD, LVSD, ESV and EDV were as follows: mm, mm, mm, cc respectively (Table 2). MR was classified as moderate in 11 patients (39.3%and severe in 17 patients (60.7%). From the echocardiography results 17 patients (60.7%) were treated medically and 11 patients (39.3%) received appointments for surgery (Table 3). The plasma NT-proBNP level in patients ranged from pg/ml to 6,431 pg/ml. The mean was 720 pg/ml. The NT-proBNP level was increased above normal in 89% of the patients. Table 2. Descriptive Statistics of Samples Descriptive Statistics Number Minimum Maximum Mean Standard Deviation EF(%) LVDD(mm) LVSD(mm) ESV(ml/m 2 ) EDV(ml/m 2 ) Table 3. Percentage of Treatment Treatment Frequency Percentage Medical Surgery Total Table 4. Severity of Echocardiography Mitral Jet Area(%) Frequency Percentage Mild Moderate Severe 8.6 Missing Total Table 5. Severity of MR Vena Contracta Frequency Percentage Width(cm) Moderate Severe Missing Total Table 6. Severity of Echocardiography EROA(cm2) Frequency Percentage Mild Moderate Severe Missing Total 100.0

5 72 Srikornruth Panyaratanakul, Tanarat Choon-ngarm, Wilai Puavilai, Saowaluk Prompongsa, Donpichit Laorakpongse, Sutham Sutheerapatranont, Anan Kriangkrichoke. By jet area 13 patients (46.4%) had moderate MRand 8 patients (.6%) had severe MR (Table 4). From VC 14 patients (50.0%) had moderate MRand 10 patients (35.7%) had severe MR (Table 5). By ERO 6 patients (21.4%) had moderate MRand17 patients (60.7%) had severe MR (Table 6). The mean of VC, EROA and jet area were 0.47 cm cm 2 and 36% respectively (Table 7). LV function show significant correlation with NTproBNP levels as describe in table 8. Levels of NTproBNP showed significant correlation (P<0.05) with the following: EF, LVDD, LVSD and EDV (Table 8), (Figure 1-5). Only one patient who needed surgery from the ACC/AHA guideline had a NT-proBNP level < 1217 pg/ml (Table 9). From the ROC data NT-proBNP at a level of 1217 pg/ml had the best sensitivity and specificity for determining whether to operate or not (Table 10), (Figure 4). The Correlation between NT-proBNP and echocardiography measurements was stronger with LVSD than EF. Table 7. Mean severity of Echocardiography Descriptive Statistics Number Minimum Maximum Mean Standard Deviation Vena Contracta Width (cm) EROA (cm 2 ) Mitral Jet Area(%) Table 8. Correlation between NT-proBNP and echocardiography variables Number Correlation P value EF(%)&NT-proBNP level LVDD(mm)&NT-proBNP LVSD(mm)&NT-proBNP ESV(ml/m 2 )&NT-proBNP EDV(ml/m 2 )&NT-proBNP Table 9. Correlation between NT-proBNP and LVSD (mm) NT-proBNP Gold Standard Gold Standard Total LVSD Surgery LVSD Medication >1217 pg/ml <1217 pg/ml Total 4 24 Sensitivity = 75.00% Specificity = 95.83% Positive predictive value = 75.00% Negative predictive value = 95.83% Prevalence = 14.29% Accuracy = 92.86%

6 NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation 73 Table 10. Correlation between NT-proBNP and EF(%) NT-proBNP Gold Standard EF Gold Standard EF Total Surgery Medication >1217 pg/ml <1217 pg/ml Total 6 22 Figure 1. Association Between NT- probnp Level vs. EF(%) Sensitivity = 33.33% Specificity = 95.45% Positive predictive value = 66.67% Negative predictive value = 84.00% Prevalence = 21.43% Accuracy = 82.14% Figure 3. Association Between NT-proBNP Level vs. LVSD(mm) Figure 2. Association Between NT-proBNP Level vs. LVDD(mm) Discussion From this study patients with moderate to severe MR who had low NT-proBNP plasma levels could be followed-up without surgery. If NT-proBNP levels were high then surgery might be needed. NTproBNP levels lower than 1,217 pg/ml showed a high predictive value for patients with preserved LV function. Obtaining an accurate qualitative vs. quantitative assessment of the severity of MR is technically demanding (2-4). For this reason a qualitative assessment of severity based on several echocardiographic measures is often used in clinical

7 74 Srikornruth Panyaratanakul, Tanarat Choon-ngarm, Wilai Puavilai, Saowaluk Prompongsa, Donpichit Laorakpongse, Sutham Sutheerapatranont, Anan Kriangkrichoke. Figure 4. Association Between NT-proBNP Level vs. ESV(ml/m 2 ) Figure 6. Association Between Sensitivity vs. Specificity Figure 5. Association Between ProBNP Level vs. EDV(ml/m 2 ) practice. In this study the natriuretic peptides and NT-proBNP increased with decreasing LV function. There was a statistically significant correlation between the LV end-systolic dimension, LV enddiastolic dimension or EF, and NT-proBNP levels. LVSD showed the strongest association with NTproBNP levels. NT-proBNP levels can be used as an indicator for follow-up instead of echocardiography. This may alleviate frequent echocardiography because of the impracticality of performing them every 6 months in provincial hospitals in Thailand due to the scarcity of skilled operators. Limitations of this investigation are the small sample number and the nature of the cross sectional study. Ideally a prospective study should be done to correlate the levels of NT-proBNP and echocardiography variables with the passage of time. Conclusion Current evidence indicates that we are operating too late on patients with chronic MR. This study demonstrates that 89% of patients with chronic MR have elevated plasma BNP concentrations. They do suggest that changes in ventricular physiology occur early in the course of the diseasebefore echocardiographic evidence of increasing LV dimensions; and that these changes vary widely between patients. There was correlation between BNP concentrations and routine echocardiography indices of LV function in this condition. Patients with chronic MR with NT-proBNP > 1,217 pg/ml probably need surgery but notwithstanding lower elevations of NT-proBNP may also be significant. NT-proBNP plasma measurements may be a useful follow- up in asymptomatic MR. Additional studies are needed to determine this prognostic indication.

8 NT-proBNP as a Marker of Left Ventricular Dysfunction in Chronic Asymptomatic Mitral Regurgitation 75 References 1. Brookes CI, Kemp MW, Hooper J, Oldershaw PJ, Moat NE. Plasma brain natriuretic peptide concentrations in patients with chronic mitral regurgitation. J Heart Valve Dis 1997; 6: Otto CM. Evaluation and management of chronic mitral regurgitation. N Eng J Med 2001; 345: Thomas L, Foster E, Hoffman JIE, Schiller NB. The mitral regurgitation index: an echocardiographic guide to severity. J Am Coll Cardiol 1999; 33: Thomas JD. How leaky is that mitral valve: Simplified Doppler methods to measure regurgitant orifice area. Circulation 1997; 95: Enriquez-Sarano M, Miller FA, Hayes SN, et al. Effective mitral regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Coll Cardiol 1995; 25: Corin WJ, Sutsch G, Murakami T, et al. Left ventricular function in chronic mitral regurgitation: preoperative and postoperative comparison. J Am Coll Cardiol 1995; 25: Bonow RO, Carabello B, McCay CR, et al. ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heat Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998; 32: Ross J Jr. The timing of surgery for severe mitral regurgitation. N Engl J Med 1996; 335: Crawford MH, Souchek J, Oprian CA, et al. Determinants of survival and left ventricular performance after mitral valve replacement. Department of Veterans Affairs Cooperative Study on Valvular Heart Disease. Circulation 1990; 81: Breisblatt W, Goodyer AV, Zaret BL, Francis CK. An improved index of left ventricular function in chronic mitral regurgitation. Am J Cardiol 1986; 57: Reed D, Abbott RD, Smucker ML, Kaul S. Prediction of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation. Circulation 1991; 84: Enriquez-Sarano M, Tajik J, Schaff HV, et al. Echocardiographic prediction of left ventricular function after correcting of mitral regurgitation: results and clinical implications. J Am Coll Cardiol 1994; 24: Enriquez-Sarano M, Schaff HV, Orszulak TA, et al. Valve repair improves the outcome of surgery for mitral regurgitation. Circulation 1995; 91: Matsumoto A, Hirata Y, Momomura S, et al. Effects of exercise on plasma level of BNP in congestive heart failure with and without left ventricular dysfunction. Am Heart J 1995; 126: Elecsys probnp, New Gold Standard, Diagnostics. Roche, 6-7, American Heart Association. Heart Disease and Stroke Statistics 2004 Update. Dallas, TX: American Heart Association; McMurray JV, McDonagh TA, Davie AP, et al. Should we screen for asymptomatic left ventricular dysfunction to prevent heart failure? Eur Heart J 1998; 19: Struthers AD. Introducing a new role for BNP: as a general indicator of cardiac structural disease rather than a specific indicator of systolic dysfunction only. Heart 2002; 87: De Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362: Sutton TM, Stewart RA, Gerber IL, et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J AM Coll Cardiol 2003; 41: 20-7.

9 76 Srikornruth Panyaratanakul, Tanarat Choon-ngarm, Wilai Puavilai, Saowaluk Prompongsa, Donpichit Laorakpongse, Sutham Sutheerapatranont, Anan Kriangkrichoke. NT-proBNP ก ก ก ก ก,.*,.** *, ก **, ก : ก ก NT probnp LV dysfunction Mitral ก ก ก : Mitral ก LV function ก ก ก ก LV function Mitral ก NT probnp ก LV function กก Echocardiography ก ก : 1 Mitral ก Echocardiography NT probnp ก ก : 15 (53.6%) 13 (46.4%), 45 Mitral 5 (17.9%), MVP 16 (57.1%), flail leaflet 6 (21.4%), 1 (3.6%) ก (EF) 68.5%, LVDD mm, LVSD mm, ก Echocardiography 17 (60.7%), 11 (39.3%) ก, NT probnp 720 pg/ml. NT - probnp กก ก 89% NT - probnp 1,217 pg/ml. LVSD ก ก : NT - probnp Echocardiography ก LV function Mitral NT probnp > 1,217 pg/ml. Mitral ก NT probnp ก Mitral