The L wave is the mid-diastolic filling wave in the

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1 Circ J doi: /circj.CJ Advance Publication by-j-stage ORIGINAL ARTICLE Heart Failure Correlates and Prognostic Values of Appearance of L Wave in Heart Failure Patients With Preserved vs. Reduced Ejection Fraction Kumiko Masai, MD; Toshiaki Mano, MD, PhD; Akiko Goda, MD, PhD; Masataka Sugahara, MD; Aika Daimon, MD; Masanori Asakura, MD, PhD; Masaharu Ishihara, MD, PhD; Tohru Masuyama, MD, PhD Background: Mid-diastolic mitral forward flow (L wave) is occasionally detected in heart failure (HF), but its correlates and prognostic value are still unknown, particularly in light of the type of HF, that is, HF with preserved or with reduced ejection fraction (HFpEF, HFrEF). Methods and Results: Of 151 patients with HF, L wave was observed in 23 of 82 HFrEF patients and in 25 of 69 HFpEF patients. Mitral early diastolic velocity (E), the ratio of E to mitral annulus velocity, and left atrial volume index were greater in the patients with L wave than in those without L wave in both subsets. Left ventricular (LV) mass index and relative wall thickness were greater in the patients with L wave than in those without L wave in the HFpEF group, but there was no difference in either parameter in the HFrEF group. Prognosis was poorer in those with L wave than in those without L wave both in the HFrEF and HFpEF groups. Conclusions: Appearance of L wave is associated with the degree of LV diastolic dysfunction, but there was a difference in LV geometrical correlates of the appearance of L wave between the HFpEF and HFrEF groups. Detection of L wave is suggestive of poor prognosis independent of LVEF in HF. Key Words: Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; L wave The L wave is the mid-diastolic filling wave in the Doppler mitral flow velocity pattern, and it is occasionally detected in patients with heart failure (HF). 1 In addition, L wave has been reported in patients with marked left ventricular (LV) hypertrophy caused by hypertension, restrictive, or hypertrophic cardiomyopathy. 2 4 The appearance of the L wave is closely related to the advanced diastolic dysfunction complicated with increased LV filling pressures. 5 Thus, the L wave is considered to be a sign of elevated LV filling pressure. Recently, it was shown that HF with L wave has poorer prognosis compared with HF without L wave in patients with normal ejection fraction (EF). 6 Thus, the detection of L wave may provide clinically useful information in patients with HF. Nevertheless, L wave has not been studied in terms of the mechanisms or determinants of its appearance and the cut-offs for assessing clinical outcome in patients with HF. HF is classified into 2 types according to LVEF: HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF). Correlates of prognosis are different between HFrEF and HFpEF. 7 9 Therefore, it is important to study the value of L wave in the estimation of prognosis in terms of the type of HF. In this study, we compared the incidence of L wave between HFrEF and HFpEF. Furthermore, we studied echocardiographic correlates of the appearance of L wave in light of the types of HF, and also compared the value of L wave in the assessment of prognosis between HFrEF and HFpEF. Methods Subjects The ethics review board at the Hyogo Collage of Medicine approved this research. This study involved 238 consecutive HF patients admitted to the Hospital of Hyogo College of Medicine between February 2013 and March The exclusion criteria were as follows: (1) associated severe valvular heart disease or prosthetic valve; (2) frequent ectopic beats or atrial fibrillation; and (3) heart rate (HR) 120 beats/min. Consequently, the subjects consisted of 151 patients: 59 women and 92 men with a mean age of 70 years. Of these, 21 patients had dilated cardiomyopathy, 52 had ischemic heart disease, and 22 had hypertensive heart disease. LVEF was assessed on echocardiography, Received April 9, 2018; revised manuscript received May 13, 2018; accepted May 23, 2018; released online July 19, 2018 Time for primary review: 28 days Cardiovascular Division (K.M., T. Mano, A.G., M.S., A.D., M.A., T. Masuyama), Coronary Heart Disease (M.I.), Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan Mailing address: Kumiko Masai, MD, Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya , Japan. kumiko-m@hyo-med.ac.jp ISSN All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Advance Publication by-j-stage MASAI K et al. Table 1. Baseline Subject Characteristics All patients HFpEF HFrEF (n=151) (n=69) (n=82) P-value Age (years) 70±15 71±5 69± Male 92 (61) 30 (43) 62 (76) <0.05 Heart rate (beats/min) 72±17 71±24 73± Hypertension 124 (82) 49 (69) 75 (91) <0.05 Diabetes mellitus 35 (23) 15 (22) 20 (24) 0.70 Dyslipidemia 35 (21) 9 (13) 23 (44) <0.05 Angina 37 (25) 10 (15) 19 (23) 0.17 PAF 42 (28) 19 (28) 23 (28) 0.94 egfr (ml/min/1.73 m 2 ) 53±30 57±32 50± Medication β-blocker 110 (72) 41 (59) 69 (84) <0.05 Calcium channel blocker 58 (38) 35 (51) 23 (28) <0.05 ACEI or ARB 106 (70) 40 (58) 66 (80) <0.05 Diuretics 78 (52) 32 (46) 46 (56) 0.23 Data given as mean ± SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; egfr, estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; PAF, paroxysmal atrial fibrillation. and those with LVEF 50% were classified as having HFpEF and others, as having HFrEF (n=69 and 82, respectively). 2-D and Doppler Echocardiography We performed echocardiography at the time of discharge. 2-D and Doppler echocardiography was performed with an available echocardiographic unit equipped with an imaging transducer having both pulsed and tissue Doppler capabilities. Images from the standard parasternal long- and short-axis views were digitally stored and reviewed. LV end-diastolic and systolic volumes were determined from 2-D echo images using the modified Simpsons method, and provided for the determination of LVEF. 10 LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), interventricular septum thickness (IVST) and posterior LV wall thickness (PWT) were routinely measured according to the American Society of Echocardiography (ASE) guideline to assess LV hypertrophy and geometry. 11 LV mass (g) was calculated using the following equation: LV mass=0.8 {1.04[(LVEDD+IVST+PWT) 3 (LVEDD) 3 ]} The value was corrected for the body surface area (LV mass index). Relative wall thickness (RWT) was calculated as (2 PWT/LVEDD). 13 Left atrial volume was measured with the modified biplane area-length method. 14,15 Pulsed Doppler mitral flow velocity pattern was recorded by placing the sample volume (size, 2 mm) between the tips of the mitral leaflets in the apical 4-chamber view. 5 The pattern was provided for the measurement of early (E) and late (A) mitral flow velocities, the ratio of early to late peak velocities (E/A) and deceleration time of early diastolic flow wave. L wave was defined as a distinct forward flow velocity curve occurred during diastasis with a peak velocity 20 cm/s. If present, the height of the L wave was determined. Early diastolic tissue velocity (e ) was measured in the mid-myocardial area of the basal LV septum, 10 mm apical to the medial mitral valve annulus. Follow-up The primary endpoint was all-cause death, and the second- ary endpoint was admission due to an exacerbation of HF. Data for death and admission were confirmed on inspection of the electronic health record. If there was no electronic health record, the data on death and admission were verified by phone contact with either the patient or the patient s family. Follow-up started at the time of the initial admission and ended in April Follow-up period ranged from 1 to 36 months (median, 17 months). Statistical Analysis All data are expressed as mean ± SD. Categorical variables are reported as number and percentage. The assumption of normality and equal variance were assessed, and parameters were compared between subgroups using Student s t-test or Mann-Whitney U-test as appropriate. Fisher s exact test was performed to evaluate proportional differences. A cumulative event-free survival curve was constructed using the Kaplan-Meier method. P<0.05 was considered to indicate statistical significance. All analyses were performed using JMP Pro (SAS, NC, USA). Results Baseline Characteristics Subject baseline characteristics are listed in Table 1. There were 69 patients with HFpEF and 82 patients with HFrEF. Mean HR was 72±17 beats/min in the whole group, and did not differ between the HFpEF and HFrEF groups. Hypertension and dyslipidemia were more prevalent in the HFpEF than in the HFrEF group. Beta-blockers and renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) were more frequently used in the HFrEF group than in the HFpEF group. In contrast, calcium channel blockers were used more often in the HFpEF than in HFrEF. Echocardiography L wave was detected in 48 of 151 patients with HF at discharge (Table 2). HR was lower in the patients with L wave than in those without L wave. In contrast, E, E/A, and E/e

3 L Wave in Heart Failure Advance Publication by-j-stage Table 2. Subject Echocardiographic Characteristics L wave (+) (n=48) All HFpEF HFrEF L wave ( ) (n=103) L wave (+) (n=25) L wave ( ) (n=44) L wave (+) (n=23) L wave ( ) (n=59) SBP (mmhg) 128±25 121±24 132±22 122±24 120±26 120±24 HR (beats/min) 65±17 75±18* 63±13 75±18* 66±10 75±17* E (cm/s) 100±28 74±31* 106±27 75±24* 93±27 74±36* e (cm/s) 4.8± ± ± ± ± ±1.3 E/e 23±10 17±9* 21±11 16±9* 25±9 18±9* E/A 1.7± ±0.7* 1.5± ±0.7* 2.0± ±0.8* L (cm/s) 37±13 38±14 35±13 TR velocity 2.7± ± ± ± ± ±0.4 LAVI (ml/m 2 ) 58±24 42±18* 56±24 38±15* 60±24 45±19* LVDd (mm) 55±10 53±10 49±5 45±7* 61±9 59±8 IVST (mm) 8.8± ± ± ± ± ±1.8 PWT (mm) 8.5± ± ± ±1.4* 7.9± ±1.6* LVDs (mm) 40±14 40±13 30±6 28±6 51±12 48±10 LVMI (g/m 2 ) 116±36 110±40 119±36 91±32* 125±32 124±38 RWT 0.31± ± ± ±0.07* 0.26± ±0.07 Data given as mean ± SD. *P<0.05, L wave (+) vs. ( ). TR velocity detected: n=40, 64, 22, 26, 18 and 38, respectively, left to right. A, late mitral inflow velocity; E, early mitral inflow velocity; e, early diastolic tissue velocity; HR, heart rate; LAVI, left atrial volume index; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVMI, left ventricular mass index; RWT, relative wall thickness; SBP, systolic blood pressure; TR, tricuspid regurgitation. Other abbreviations as in Table 1. Figure 1. Ratio of early mitral inflow velocity to early diastolic tissue velocity (E/e ), left ventricular mass index (LVMI), and relative wall thickness (RWT) in (A) heart failure (HF) with preserved ejection fraction (HFpEF) and (B) HF with reduced ejection fraction (HFrEF) patients according to L wave status. Boxes, upper and lower quartile with the median marked by the center line; error bars, spread between 5th and 95th percentiles.

4 Advance Publication by-j-stage MASAI K et al. Table 3. Echocardiographic Indicators of L Wave in HFpEF Univariate Multivariate OR 95% CI P-value OR 95% CI P-value E (cm/s) <0.05 e (cm/s) E/e < E/A <0.05 LAVI (ml/m 2 ) <0.05 LVDd (mm) <0.05 LVDs (mm) LVMI (g/m 2 ) < <0.05 RWT (0.1 decrease) < Abbreviations as in Tables 1,2. Table 4. Echocardiographic Indicators of L Wave in HFrEF Univariate Multivariate OR 95% CI P-value OR 95% CI P-value E (cm/s) <0.05 e (cm/s) E/e < <0.05 E/A <0.05 LAVI (ml/m 2 ) <0.05 LVDd (mm) LVDs (mm) LVMI (g/m 2 ) RWT (0.1 decrease) <0.05 Abbreviations as in Tables 1,2. were greater in those with L wave than in those without L wave. LA volume index was also greater in those with L wave than in those without L wave. The same findings were observed in the HFpEF and in the HFrEF groups (Table 2). When the data were analyzed for the HFpEF group, however, LV mass index and RWT were greater in the patients with L wave than in the patients without L wave. In contrast, there was no significant difference in LV mass index or RWT according to L wave status in the HFrEF group (Figure 1). LV mass index was independently associated with L wave in the HFpEF group, but not in the HFrEF group (Tables 3,4). In the HFrEF group, E/E ratio and RWT were independently associated with the presence of L wave (Table 4). Clinical Outcomes Median follow-up was 17 months (range, 1 36 months). Thirty-nine patients (26%) died (of whom 26 [17%] died due to cardiovascular events), and 55 (36%) were admitted due to an exacerbation of HF during the follow-up period (Figure 2). Of note, the outcome was better in patients without L wave than in those with L wave at discharge (Figure 2). Discussion In the present study, L wave was associated with diastolic dysfunction in both the HFpEF and HFrEF groups. The presence of L wave was associated with LV geometrical change, specifically concentric remodeling and concentric hypertrophy, in the HFpEF group. Although the correla- tions for the L wave differed between HFpEF and HFrEF, long-term prognosis was equally poorer in patients with L wave than in those without L wave, independent of EF. The appearance of the L wave was correlated with E/e both in the HFpEF and in the HFrEF groups. An increase in E wave indicates an increase in the LA-LV pressure gradient at the mitral valve opening, and the LA enlargement indicates chronic increase in LA pressure. This was observed in patients with L wave regardless of HFpEF or HFrEF, and it is considered that an increase in LA pressure is essential in the appearance of L wave. In fact, L wave was not observed in patients with relaxation abnormality mitral flow velocity pattern, but in patients with pseudonormalized or restrictive pattern. Ha et al clearly showed that advanced diastolic dysfunction and increased LV filling pressures were important determinants of L wave in their subjects, 17% of whom had HF. 16 The present findings were partially inconsistent with theirs, because in the present study there was no difference in e velocity according to L wave status. LA pressure may increase as a consequence of myocardial diastolic dysfunction, but LA pressure may increase even without any alteration in the myocardial property, and instead may increase as a result of LV geometrical change or simple preload augmentation. We found that preload augmentation (leg lifted and i.v. infusion of normal saline 500 ml) resulted in the appearance of L wave in a patient with HFpEF (Figure 3). Thus, the presence of L wave cannot be used as an indicator of severely damaged myocardial (diastolic) function. We showed that LV geometrical alteration such as concentric remodeling and concentric hypertrophy are related to the

5 L Wave in Heart Failure Advance Publication by-j-stage Figure 2. Kaplan-Meier curves for cumulative rate of survival and admission for heart failure (HF) in (A) HF with preserved ejection fraction (HFpEF) and (B) HF with reduced ejection fraction (HFrEF) patients according to L wave status. Figure 3. Representative mitral flow velocity patterns at (A) rest and (B) after preload augmentation in the same subject. A, late mitral inflow velocity; E, early mitral inflow velocity; e, early diastolic tissue velocity. It is easily anticipated that LA pressure increases with impairment of LV myocardial (diastolic) function, such as in the presence of myocardial degradation and fibrosis in patients with HFrEF. There was a tendency for the L wave to be associated with LV remodeling (enlargement) and decreased e velocity in patients with HFrEF. Although one might expect that advanced myocardial damage conappearance of L wave, particularly in the HFpEF group. It is reasonable that such LV geometrical alterations contribute to the elevated LA pressure even without any alteration in the myocardial parameters. The L wave has been observed in patients with LV hypertrophy, but with preserved EF, 1 and the mechanism of the L wave in these patients may be explained this way.

6 Advance Publication by-j-stage MASAI K et al. tributes to the appearance of L wave, particularly in patients with HFrEF, this was not seen in the present study, and future studies are necessary to clarify this. Prognosis was poorer in those with L wave than in those without L wave, both in the HFrEF and the HFpEF groups. Kim et al noted poor long-term clinical outcome in patients with L wave. 6 They analyzed only patients with normal EF, and only approximately 30% of the subjects had HF. That conclusion was similar to the present one, but we analyzed only patients with HF. In the present study we noted that the mechanisms of the L wave may be different between HFpEF and HFrEF. 17 The appearance of L wave is a sign of poor prognosis regardless of the mechanism of the L wave in individual patients. Study Limitations This was a single-center study with a relatively small number of patients. Additional multicenter studies are required to reconfirm the results in a larger number of patients. Given that catheterization data were available only for selected patients, echocardiographic data were used as correlates in this study. HR is a well-known determinant of L wave, 5 and therefore, we excluded patients with HR 120 beats/min in this study. HR was certainly lower in patients with L wave than in patients without L wave in both HF subgroups in this study. It is likely that the L wave may disappear if HR increases in some patients with L wave, while L wave may appear if HR decreases in some patients without L wave. Thus, we can say only that the absence of L wave does not necessarily imply good outcome if the patient has high HR at that moment. Future studies are necessary to clarify the effect of HR on the appearance of L wave. Finally, approximately one-quarter of the present patients had paroxysmal atrial fibrillation (PAF). It is known that mitral flow velocity pattern changes immediately after the return from atrial fibrillation to sinus rhythm, and that it takes a while for the pattern to return to that at sinus rhythm. 17 We therefore confirmed that no patient had an episode of atrial fibrillation immediately before echocardiography. When we compared A wave between patients with and without PAF, there was no significant difference (66±32 vs. 75±24 cm/s), and the incidence of L wave was similar between patients with and without PAF (37% vs. 30%, P=n.s.). The inclusion of such patients was therefore unlikely to affect the present conclusion. Acknowledgments We thank Masumi Tanaka, Sachiko Makihara, Chika Misumi, and Kumiko Matsunaga for their excellent technical support. Disclosures The authors declare no conflicts of interest. None. Funding / Disclosures References 1. Lam CS, Han L, Ha JW, Oh JK, Ling LH. 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