Practical Impact of New Diastolic Recommendations on Noninvasive Estimation of Left Ventricular Diastolic Function and Filling Pressures

Practical Impact of New Diastolic Recommendations on Noninvasive Estimation of Left Ventricular Diastolic Function and Filling Pressures Regina Sorrentino, MD, Roberta Esposito, MD, PhD, Ciro Santoro, MD, Andrea Vaccaro, MD, Sara Cocozza, MD, PhD, Maria Scalamogna, MD, Maria Lembo, MD, Federica Luciano, MD, Alessandro Santoro, MD, Bruno Trimarco, MD, and Maurizio Galderisi, MD, Naples and Mercogliano, Italy

Background: In 2016, an update of the 2009 recommendations for the evaluation of left ventricular (LV) diastolic function (DF) was released by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. The aims of this study were to assess the concordance between the 2016 and 2009 recommendations and to test the impact of the consideration of ‘‘myocardial disease’’ recommended in the 2016 update on the evaluation of diastolic dysfunction (DD) and LV filling pressures in patients with normal and reduced LV ejection fractions referred to a general echocardiography laboratory. Methods: A total of 1,508 outpatients referred to an echocardiography laboratory during a predefined 5-month period were prospectively enrolled. All patients underwent targeted clinical history and Doppler echocardiographic examination. DD and LV filling pressures were assessed according to 2009 and 2016 recommendations. Concordance was calculated using the k coefficient and overall proportion of agreement. Results: Overall proportion of agreement between the two recommendations was 64.7% (k = 0.43). Comparing the 2009 and 2016 recommendations, 47.5% and 36.1% patients, respectively, had DD (P < .0001), and 22.7% and 12.6% had elevated LV filling pressures (P < .0001). This difference remained significant in the setting of patients with normal LV ejection fractions (21.6% vs 10.7%, P < .0001). In the application of the 2016 recommendations, whether or not the presence of ‘‘myocardial disease’’ was considered, the prevalence of indeterminate diastolic function was, respectively, 7.3% versus 13.7%, while patients in whom the DD grade could not be determined were 8.1% versus 14.4% (P < .0001 for all). Conclusions: Considering the presence of myocardial disease when applying the 2016 recommendations resulted in a lower prevalence of inconclusive diagnosis. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Left ventricular filling pressures, Diastolic function, Doppler echocardiography, Myocardial disease, Recommendations

Left ventricular (LV) diastolic dysfunction (DD) and, by extension, impaired LV filling pressures (LVFPs) are among the main determinants of decompensation, symptoms, and prognosis in patients with heart failure.1-3 Accordingly, Doppler echocardiographic evaluation of LV diastolic function (DF) is of pivotal importance for

From the Department of Advanced Biomedical Sciences, Federico II University Hospital, Naples (R.S., R.E., C.S., M.S., M.L., A.S., B.T., M.G.); and the Coronary Care Unit, Clinica Montevergine, Mercogliano (A.V., S.C., F.L.), Italy. Drs. Sorrentino, Santoro, and Lembo are supported by the International PhD Programme in Cardiovascular Pathophysiology and Therapeutics. Conflicts of Interest: None. Reprint requests: Maurizio Galderisi, MD, Interdepartmental Laboratory of Cardiac Imaging, Federico II University Hospital, Via Pansini 5, 80131 Naples, Italy (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.08.013

comprehensive clinical assessment and therapeutic management of patients.4-6 Doppler echocardiographic estimates of LV DD and increased LVFP have widely shown their prognostic value in the clinical setting.7-9 Moreover, integrated Doppler echocardiographic estimates of LVFP have been tested and validated against simultaneous invasive measurements of LVFP (i.e., heart catheterization).10-14 In 2016, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) released an updated version15 of the recommendations for the evaluation of LV DF and the estimation of LVFP by Doppler echocardiography, previously published in 2009.16 The updated recommendations promote a practical approach for DD diagnosis and LVFP estimation, pointing out the most useful, reproducible, and feasible twodimensional echocardiographic and Doppler measurements with the goal of increasing their utility in daily clinical practice. New recommendations suggest a two-step process. The first work flow, to be applied in patients with normal LV ejection fractions (LVEFs; $53%), allows echocardiographic diagnosis of DD. The second 1

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work flow is indicated for the estimation of LVFP and DD Ar-A = Atrial reverse– grading in patients with DD, in transmitral A those with reduced LVEFs (<53%), and in those with ASE = American Society of normal LVEFs and significant Echocardiography ‘‘myocardial disease’’ (e.g., presCAD = Coronary artery ence of LV hypertrophy [LVH], disease ischemic or significant valvular DD = Diastolic dysfunction heart disease). The 2016 recommendations DF = Diastolic function have been validated in recent DT = Deceleration time multicenter studies against invasive measurements obtained by EACVI = European cardiac catheterization, showing Association of Cardiovascular good accuracy.11-14 Their use Imaging has shown a good level of EROA = Effective regurgitant agreement and accuracy in the orifice area estimation of invasive LVFP, ICC = Intraclass correlation irrespective of the experience coefficient level of the observer.17 Almeida et al.18 retrospectively evaluated IVC = Inferior vena cava the impact of the 2016 recomIVRT = Isovolumic relaxation mendations in comparison with time the 2009 version in a large population of patients with normal LAVi = Left atrial volume LVEFs, showing poor concorindex dance and a significantly lower LV = Left ventricular rate of DD when applying the LVEF = Left ventricular 2016 recommendations. This ejection fraction was consistent the findings of another population-based reLVFP = Left ventricular filling search letter.19 However, both pressure studies applied the 2016 recomLVH = Left ventricular mendations incorrectly, as they hypertrophy did not assimilate patients with myocardial disease to those PASP = Pulmonary artery systolic pressure with DD. In the present study, we proRAP = Right atrial pressure spectively evaluated the concorTR = Tricuspid regurgitation dance of the ASE/EACVI 2009 and 2016 recommendations in the diagnosis of DD and in the estimation of LVFP in consecutive patients, with normal and reduced LVEFs, referred to our echocardiography laboratory. Moreover, we tested the impact of ‘‘myocardial disease’’ on the prevalence and grading of DD according to the 2016 recommendations. Abbreviations

METHODS Study Population The Interdepartmental Laboratory of Echocardiography of the Federico II University Hospital of Naples is a general echocardiography laboratory examining mainly outpatients affected by multiple diseases, including an important percentage of oncology patients. In the present study we included consecutive adult patients (age > 18 years) prospectively referred to our laboratory for multiple indications, in a predefined period of 3 months (from January to March 2018). Moreover, in an additional 2-month period (November to

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December 2018), we prospectively enrolled only patients without oncologic indications, to obtain a population that could be more reflective of other general outpatient echocardiography laboratories at which oncology patients represent a relatively smaller proportion of the referral population. A targeted history and measurements of blood pressure and heart rate were obtained at the time of the echocardiographic exam. Exclusion criteria were severe mitral annular calcification, ventricular pacing, presence of a prosthetic valve, mitral stenosis of any grade, severe mitral valve regurgitation, hypertrophic and restrictive cardiomyopathies, and atrial fibrillation (at the time of the echocardiographic examination). In these settings the 2016 recommendations require the determination of additional specific parameters. Moreover, we excluded patients with severe aortic stenosis in presence of severe mitral annular calcification and those with severe aortic regurgitation because of its possible interference with the recording of mitral inflow velocities. All participants gave their written informed consent. Procedures Doppler echocardiographic examinations were performed according to the standards of our laboratory20 using Vivid E95, Vivid E9, and Vivid 7 ultrasound machines (GE Vingmed Ultrasound, Horten, Norway) equipped with a 2.5-MHz transducer with harmonic capability, and the echocardiography report was prepared according to EACVI standardization.21 Quantitative analysis was performed according to guidelines.22 LVEF < 53% was considered reduced.22 Left atrial volume22 and LV mass were indexed to body surface area.22 LV mass index >95 g/m2 in women and >115 g/m2 in men defined the presence of LVH. Doppler-derived transmitral inflow early (E) and atrial (A) peak velocities, E/A ratio, E-velocity deceleration time (DT), pulsed tissue Doppler of the septal and lateral annulus (early diastolic velocity [e0 ]), average E/e0 ratio, and tricuspid regurgitation (TR) jet peak velocity were determined in the apical fourchamber view according to 2016 recommendations.15 The estimation of pulmonary artery systolic pressure (PASP) was based on TR peak velocity and application of the simplified Bernoulli equation and adding to that right atrial pressure (RAP). RAP was estimated according to ASE guidelines, on the basis of the size of the inferior vena cava (IVC) and the degree of its inspiratory collapse during normal respirations: (1) normal RAP (5 mm Hg) on the basis of normal IVC size (IVC diameter < 2.1 cm) with normal inspiratory collapse (>50% decrease in IVC diameter); (2) RAP  10 mm Hg: dilated IVC (diameter > 2.1 cm) or <50% collapse; (3) RAP  15 mm Hg: both dilated IVC and <50% collapse; and (4) RAP  20 mm Hg: dilated IVC without visible collapse.23 Presence and grade of valvular heart disease were evaluated using an integrated approach according to European recommendations.24 We used qualitative methods (color Doppler flow and continuous Doppler intensity) for mild valvular disease and quantitative methods (vena contracta or proximal isovelocity surface area–derived effective regurgitant orifice area, peak velocity, mean anterograde gradient, and continuity equation–derived functional valve area for stenoses) for moderate to severe valvular heart disease. In patients with moderate mitral regurgitation, speckle-tracking-derived LV global longitudinal strain was quantified using Automated Function Imaging (GE Vingmed Ultrasound) according to the standards of our laboratory.25 DD and LVFP were evaluated, in the same population, according to the 2009 and 2016 recommendations.15,16 Grading of DD and estimation of LVFP were assessed through a fixed algorithm provided to SPSS software (IBM, Armonk, NY).

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HIGHLIGHTS  We tested concordance between 2009 and 2016 recommendations in an outpatient setting.  The use of 2016 recommendations results in a lower rate of diastolic dysfunction.  Fewer patients are diagnosed with increased left ventricular filling pressures.  The introduction of tricuspid regurgitation velocity seems to a be decisive parameter.  Considering patients’ myocardial disease reduces the rate of indeterminant conclusions. According to the 2009 recommendations,16 normal DF was attributed to patients with septal e0 $ 8 cm/s, lateral e0 $ 10 cm/ sec, and left atrial volume index (LAVi) < 34 mL/m2. In patients with septal e0 < 8 cm/sec or lateral e0 < 10 cm/sec and LAVi $ 34 mL/m2, DD was graded from 1 to 3 on the basis of at least two measures among average E/e0 (E # 8, between 9 and 12, and $13 cm/sec, respectively), mitral inflow E/A ratio (<0.8, between 0.8 and 1.2, and >2, respectively), and DT (>200, between 160 and 200, and <160 msec, respectively) reaching the given cutoffs. The evaluation of LVFP was done using two separate algorithms in patients with reduced and normal LVEFs. In patients with reduced LVEFs, we considered LVFP as normal in presence of E/A ratio < 1 and E # 50 cm/sec and elevated for E/A ratio $ 2 and DT < 150 msec. In the intermediate range of E/A ratio ($1 and <2 or for E/A ratio < 1 and E > 50 cm/sec), we used average E/e0 ratio > 15 and/or PASP > 35 mm Hg to designate elevated LVFP and E/e0 ratio < 8 and PASP < 30 mm Hg to define normal LVFP. In patients with normal LVEFs, the estimation of LVFP was based on average E/e0 ratio: normal LVFP when E/e0 # 9 and elevated LVFP when average E/e0 $ 13; elevated LVFP was also defined when E/e0 ratio ranged from 9 to 13 with concomitant presence of LAVi $ 34 mL/m2 and/or PASP > 35 mm Hg. Moreover, because the 2009 recommendations did not clearly identify an indeterminate grading, DD and LVFP were considered indeterminate if no precise conclusion or even discordant conclusion was reached with the given cutoff points. The 2016 recommendations15 provide a two-step approach. In patients with normal LVEFs, the recommendations suggest the use of four variables to determine the presence of DD (septal e0 < 7 cm/s or lateral e0 < 10 cm/s, average E/e0 ratio > 14, TR velocity > 2.8 m/sec, and LAVi > 34 mL/m2) and to grade DF as normal, indeterminate, or abnormal. Patients are diagnosed with DD if >50% of the variables are positive, while the evaluation of DF is inconclusive and thus DF is graded ‘‘indeterminate’’ if exactly 50% of the available variables are positive. In patients with reduced LVEFs, and in those with normal LVEFs but evidence of ‘‘myocardial disease’’ or DD, a second algorithm allows the estimation of LVFP and thus grading of DD. We considered as ‘‘myocardial disease’’ LVH, coronary artery disease (CAD) in the presence of regional wall motion abnormalities, moderate aortic regurgitation and stenosis, and secondary moderate mitral regurgitation or primary mitral regurgitation in the presence of reduced LV global longitudinal strain (<20%22), LVH, or a combination of these two abnormalities. By this algorithm, LVFP was considered increased for E/A ratio $ 2 or E/A ratio # 0.8 along with E velocity > 50 cm/sec, or for E/A ratio > 0.8 to <2 and at

least two of the following criteria were observed: average E/e0 ratio $ 14, LAVi $ 34 mL/m2, and TR velocity $ 2.8 m/sec. Accordingly, DD was assessed as grade I, grade II, grade III, or ‘‘cannot determine’’ if LVFP could not be estimated because of discrepancy between the only two available parameters or presence of only one available parameter. It is important to note that the ‘‘indeterminate’’ DF and ‘‘cannot determine’’ DD grades have different meanings in the 2016 recommendations. Notably, we decided a priori not to use some parameters, such as pulmonary venous flow–derived systolic-to-diastolic ratio, atrial reverse–transmitral A (Ar-A) difference, and Valsalva delta E/A ratio (suggested in both the 2009 and 2016 recommendations), on the grounds of previously reported lower feasibility10 and reproducibility26,27 data. Transmitral E velocity/velocity flow propagation ratio and isovolumic relaxation time (IVRT)/TE-e0 ratio, suggested in the 2009 recommendations, were not evaluated because, at the present time, their use is suggested only in particular settings (mitral stenosis and atrial fibrillation) that were excluded from the present study. Feasibility and temporal—day-to-day (within 24 hours)—reproducibility (on two different images acquired on two different days) of some diastolic parameters, including E-velocity DT, IVRT (measured by placing the pulsed sample volume between the LV inflow and LV outflow tract in the apical long-axis view), percentage variation of post-Valsalva E velocity, and Ar-A difference, were tested in a subset of 50 patients. Statistical Analysis Grading of DD and estimation of LVFP were assessed using a fixed algorithm provided to SPSS release 12. All data are expressed as mean 6 SD for continuous data. We used a binary coding method for each of the variables indicated in the recommendations (E/A ratio, E/e0 ratio, septal or lateral e0 , TR velocity, LAVi, PASP, and septal and lateral e0 ) and then assessed the presence and grading of DD and LVFP according to each algorithm, on the basis of the number of impaired parameters. Moreover, when applying the 2016 update, to evaluate the impact of considering versus not considering the presence of ‘‘myocardial disease,’’ patients with myocardial disease were assigned a specific code and analyzed with and without application of the code. Statistical differences between continuous variables were tested using the unpaired Student’s t test or the equivalent nonparametric procedure (Mann-Whitney U test) for variables not normally distributed. The concordance between classification methods for the determination of DD and LVFP according to 2009 and 2016 recommendations was tested by calculating the k coefficient and the overall proportion of agreement. Concordance was defined as slight (0–0.20), fair (0.21–0.40), moderate (0.41–0.60), good (0.61–0.80), or optimal (0.81–1). The overall proportion of agreement expressed the proportion of observations identically classified between the two algorithms. The day-to-day variability of chosen variables was assessed by calculating intraclass correlation coefficients (ICCs) and their 95% CIs. The null hypothesis was rejected at P # .05.

RESULTS We enrolled 1,508 consecutively eligible adult outpatients (51% women, 49% men; age range, 18–97 years). In the recruited population, 379 patients had arterial hypertension (25.1%), 147 had type 2

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Table 1 Characteristics of the study population LVEF $ 53% (n = 1,378)

All (N = 1,508)

57.6 6 15.1

56.9 6 15.1

64.5 6 11.9

<.0001

Systolic BP, mm Hg

129.9 6 17.3

129.8 6 17.1

130.1 6 18.5

.859

Diastolic BP, mm Hg

77.8 6 10.1

78.0 6 10.0

76.6 6 11.5

.136

Heart rate, beats/min

71.5 6 11.4

76.6 6 11.5

71.5 6 11.3

.472

LV end-diastolic dimension, mm

49.2 6 5.3

48.6 6 4.7

55.4 6 7.1

<.0001

LV end-systolic dimension, mm

31.9 6 5.5

31.3 6 4.8

40.1 6 7.3

<.0001

LV relative wall thickness

0.36 6 0.7

0.36 6 0.7

0.35 6 0.7

.016

LV mass/BSA, m2

84.4 6 23.2

81.9 6 20.8

110.6 6 30.9

<.0001

LVEF, %

59.4 6 6.4

60.8 6 4.1

44.0 6 6.4

<.0001

Age, y

LVEF < 53% (n = 130)

P

Parameter

74.8 6 19.1

75.2 6 18.3

69.9 6 25.6

.003

E-velocity DT, msec

232.9 6 54.8

232.1 6 53.1

241.2 6 69.5

.072

Transmitral E/A ratio

1.0 6 0.4

1.01 6 0.3

0.96 6 0.5

.124

Septal e0 velocity, cm/sec

7.6 6 2.7

7.8 6 2.6

5.4 6 2.1

<.0001

Lateral e0 velocity, cm/sec

10.1 6 3.6

10.4 6 3.6

7.1 6 3.1

<.0001

9.2 6 4.0

8.9 6 3.7

11.9 6 5.7

<.0001

LAVi, mL/m2

29.6 6 8.7

28.9 6 8.1

36.7 6 12.8

<.0001

TR velocity, m/sec

2.47 6 0.6

2.5 6 0.6

2.6 6 0.4

.146

PASP

30.0 6 7.2

29.9 6 7.0

32.3 6 8.9

<.0001

E velocity, cm/sec

E/e0 ratio

BP, Blood pressure; BSA, body surface area. Data are expressed as mean 6 SD. Bold text indicates statistical significance.

diabetes mellitus (9.7%), and 82 had obesity (5.4%). Histories of CAD were found in 208 patients (13.8%) and stroke in 38 (2.5%). Oncologic disease was present in 390 patients (25.9%); among these, 60.8% had already received chemotherapy and/or radiotherapy at the time of echocardiographic examination. Significant mitral valve regurgitation was found in 7.3% of patients (n = 110), of whom 83 had primary mitral valve regurgitation and 27 had secondary mitral valve regurgitation. Significant aortic valve disease (both regurgitation and stenosis) was found in 6.4% (n = 96). Among the remaining 213 patients (16.8%), 20 patients (1.3%) had chronic nephrologic disease, 34 patients (2.2%) had rheumatologic disease, and 88 patients (5.8%) had endocrinologic disease. Cardiac involvement (including LVH, more than mild valvular heart disease, reduced LVEF, and pulmonary artery hypertension) was present in 11 patients (32.3%) with rheumatologic disorders and 14 patients (15.9%) with endocrinologic disorders (data not shown). Demographic and echocardiographic characteristics of the pooled population and of the subgroups with normal and reduced LVEF are presented in Table 1. A total of 130 patients (8.6%) had reduced LVEFs (<53%). They were older, had larger LV diameters and left atria, had higher LV mass index values, had lower e0 velocities, had higher E/e0 ratios, and had higher TR velocities compared with patients with normal LVEFs. There were 348 patients (25.3%) assigned with ‘‘myocardial disease’’ (Table 2). Patients with normal LVEFs and ‘‘myocardial disease,’’ compared with those without it, were more frequently women, were older, had higher systolic blood pressure, had lower heart rates, had larger LV end-diastolic diameters, and, although within the normal range, had lower LVEFs. As expected, this subpopulation also had larger left atria, higher LV mass index values and relative wall thickness, lower e0 velocities, higher E/e0 ratios, and higher TR velocities.

Diastolic Function DD estimates according to both recommendations in the overall population and in the subgroups with reduced and normal LVEFs are presented in Table 3. The prevalence of normal DF was 52.5% according to the 2009 recommendations and 56.6% according to the 2016 recommendations (P = .02), and the prevalence of DD was 47.5% versus 36.1%, respectively (P < .0001). No patient had indeterminate DF according to the 2009 recommendations, whereas 7.3% had indeterminate DF according to the 2016 update (P < .0001). LVFPs and DD Grading The prevalence of normal LVFP was 75.3% with the 2009 recommendations versus 79.3% with the 2016 recommendations (P = .01). The prevalence of elevated LVFP was 22.7% and 12.6%, respectively (P < .0001), this difference being significant even in the subgroup with normal LVEFs (21.6% vs 10.7%, P < .0001), whereas 1.9% versus 8.1% (P < .0001) had LVFP graded ‘‘cannot determine’’ (Table 3). Notably, TR velocity was not obtainable in 94 patients (6.2% of the total population). Among the 122 patients in whom DD grade could not be determined with the 2016 recommendations, 110 patients (90.2%) were graded with ‘‘indeterminate’’ DD according to the first algorithm, and in only 12 patients (10.5%), LVFP could not be evaluated because of missing TR velocity and discordance between the only two available parameters (data not shown).

Subanalyses in Particular Groups Separate subanalyses in patients with LVH and in those with valvular heart disease showed the expected higher prevalence of grade I DD (P < .0001 for all) and lower prevalence of increased

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Table 2 Characteristics of the subgroup with normal LVEFs according to the presence of myocardial disease LVEF > 53%, no myocardial disease (n = 1,030)

LVEF > 53% and myocardial disease (n = 348)

P

53.9 6 15.0

65.9 6 11.5

<.0001

546 (53.0)

160 (46.0)

.02

Mitral regurgitation

50 (4.8)

38 (10.9)

<.0001

Aortic regurgitation

—

66 (16.6)

—

Aortic stenosis

—

14 (3.5)

— —

Parameter

Age, y Sex, female

CAD

—

152 (38.2)

LVH

—

170 (42.7)

—

Systolic BP, mm Hg

128.4 6 16.7

133.1 6 17.8

<.0001

Diastolic BP, mm Hg

78.1 6 10.9

77.5 6 9.7

.322

Heart rate, beats/min

72.6 6 11.6

68.5 6 10.2

<.0001

LV end-diastolic dimension, mm

48.0 6 4.4

50.2 6 5.2

<.0001

LV end-systolic dimension, mm

30.9 6 4.4

32.1 6 5.6

<.0001

LV relative wall thickness

0.35 6 0.6

0.39 6 0.7

<.0001

LV mass/BSA, m2

75.9 6 15.5

99.7 6 24.1

<.0001

LVEF, %

61.2 6 4.0

59.8 6 4.2

<.0001

E velocity, cm/sec

75.8 6 18.6

73.6 6 17.3

.056

E-velocity DT, msec

226.9 6 51.2

247.6 6 55.8

<.0001

Transmitral E/A ratio

1.06 6 0.3

0.88 6 0.3

<.0001

Septal e0 v elocity, cm/sec

8.3 6 2.6

6.3 6 1.9

<.0001

Lateral e0 velocity, cm/sec

11.0 6 3.5

8.4 6 2.8

<.0001

E/e0 ratio

8.3 6 3.5

10.6 6 3.7

<.0001

LAVi, mL/m2

27.4 6 6.7

33.2 6 9.8

<.0001

TR velocity, m/sec

2.42 6 0.6

2.6 6 0.4

<.0001

PASP

28.9 6 6.3

32.4 6 8.2

<.0001

BP, Blood pressure; BSA, body surface area. Data are expressed as mean 6 SD or as number (percentage). Bold text indicates statistical significance.

LVFP and of grade II DD when applying the 2016 recommendations rather than the 2009 recommendations (P < .001 and P < .0003, respectively). Conversely, patients with CAD showed a higher prevalence of grade I DD (P < .0001), and the difference

in the prevalence of grade II DD did not achieve statistical significance (P = .07). Gender-specific comparison between the 2016 and 2009 recommendations showed a lower prevalence of grade II DD and a higher prevalence of ‘‘cannot determine’’ DD grade in both genders (P < .0001 for all when applying the 2016 recommendations), whereas no significant difference in prevalence of grade I DD was found. We also evaluated the impact of cancer therapy on LV DF in our oncology population. Comparing patients with cancer who received or were receiving chemotherapy or radiation therapy at the time of the examination with those whose assessments were made before starting therapy, we found no significant difference in the prevalence and grading of DD with both the 2016 and 2009 recommendations (data not shown). However, in oncology patients who received or were receiving chemotherapy or radiation therapy at the time of the examination, the rates of DD and increased LVFP with the new recommendations were 24.5% and 8.9%, respectively. Patients who received chemotherapy or radiation therapy, compared with those who did not, showed no significant difference in LVEF (61.1% vs 60.1%, P = .198). Feasibility and Reproducibility Analysis In a sample of 50 patients, feasibility was 100% for transmitral E/A ratio, E/e0 ratio, and IVRT, whereas feasibility of the Valsalva maneuver was 72% (36 of 50) and of Doppler-derived pulmonary venous flow was 70% (35 of 50). The day-to-day variability of Doppler parameters was as follows: E/A ratio: ICC = 0.957 (95% CI, 0.925– 0.976; P < .0001); DT: ICC = 0.778 (95% CI, 0.608–0.784; P < .0001); E velocity post-Valsalva percentage change: ICC = 0.618 (95% CI, 0.255–0.805; P = .003); E/e0 ratio: ICC = 0.948 (95% CI, 0.908–0.971; P < .0001); IVRT: ICC = 0.699 (95% CI, 0.473–0.829; P < .0001); and Ar-A: ICC = 0.776 (95% CI, 0.561–0.886; P < .0001). Normal LVEF with Myocardial Disease In addition to the 2016 recommendations, we also compared DF, LVFP, and DD grade, applying the first-step decision algorithm to all patients with normal LVEFs. Table 4 shows the impact of the consideration of ‘‘myocardial disease’’ on estimates of DD, LVFP, and grading of DD according to 2016 recommendations in the overall population and in the subpopulation with normal LVEFs and myocardial disease. In the overall population, assuming or not assuming the presence of ‘‘myocardial disease,’’ according to the first algorithm, the prevalence of ‘‘indeterminate’’ DF was 7.3% versus 13.7% (P < .0001), whereas according to the second algorithm, grading of DD was not achievable (‘‘cannot determine’’ DD grade) in 8.1% versus 14.4%, respectively (P < .0001; Figure 1). The same results were found in the subpopulation with both normal LVEFs and ‘‘myocardial disease,’’ in which 0.6% versus 27.3% of patients had the ‘‘cannot determine’’ designation if ‘‘myocardial disease’’ was considered. Figure 2 depicts an example of a patient with normal LVEF in whom the assumption of ‘‘myocardial disease’’ makes the difference.

Concordance and Reclassification Overall proportion of agreement for DD diagnosis between the two recommendations was 64.7% (DD diagnosis agreed in 975 patients,

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Table 3 Estimates of DD and LVFP and grading of DD according to 2009 and 2016 recommendations LVEF $ 53% (n = 1,378)

All (N = 1,508) Diastolic function

LVEF < 53% (n = 130)

P

2009

2016

854 (56.6)

.02

791 (57.4)

854 (62.0)

.01

0

0

1

544 (36.1)

<.0001

587 (42.6)

414 (30.0)

<.0001

130 (100)

130 (100)

1

0*

110 (7.3)

<.0001

0*

110 (8.0)

<.0001

0*

0

1 <.001

2009

2016

Normal DF

791 (52.5)

DD

717 (47.5)

Indeterminate DF* Normal LVFP

P

2009

2016

P

1,136 (75.3)

1,196 (79.3)

.01

1,078 (78.2)

1,112 (80.7)

.119

58 (44.6)

84 (64.6)

Increased LVFP

343 (22.7)

190 (12.6)

<.0001

297 (21.6)

148 (10.7)

<.0001

46 (35.4)

42 (32.3)

.694

Grade I DD

345 (22.9)

342 (22.7)

.930

287 (20.8)

258 (18.7)

.180

58 (44.6)

84 (64.6)

<.001

Grade II DD

330 (21.9)

177 (11.7)

<.0001

292 (21.2)

143 (10.4)

<.0001

38 (29.2)

34 (26.2)

.677

Grade III DD

13 (0.9)

13 (0.9)

$.999

5 (0.4)

5 (0.4)

$.999

8 (6.2)

8 (6.2)

$.999

Cannot determine DD grade*

29 (1.9)*

122 (8.1)

<.0001

3 (0.2)*

118 (8.6)

<.0001

26 (20)

4 (3.1)

<.0001

Data are expressed as number (percentage). Bold text indicates statistical significance. *The 2009 recommendations do not take into account a specific category for patients not meeting the given criteria and in which assessment of DF and DD grade is not possible.

Table 4 Impact of the consideration of myocardial disease on the estimates of DD and LVFP and grading of DD according to the 2016 recommendations in the overall population and in the subpopulation with normal LVEFs and myocardial disease Considering myocardial disease

Not considering myocardial disease

P

Normal DF

854 (56.6)

1023 (67.8)

<.0001

DD

544 (36.1)

279 (18.5)

<.0001

Indeterminate DF*

110 (7.3)

206 (13.7)

<.0001

1,196 (79.3)

1,108 (73.5)

.0002

Increased LVFP

190 (12.6)

183 (12.1)

NS

Grade I DD

342 (22.7)

85 (5.6)

<.0001

Grade II DD

177 (11.7)

172 (11.4)

NS

Grade III DD

13 (0.9)

11 (0.7)

NS

Cannot determine DD grade*

122 (8.1)

217 (14.4)

<.0001

Diastolic function

Overall population (N = 1,508)

Normal LVFP

LVEF > 53% and myocardial disease (n = 348) Normal DF

0 (0)

170 (48.9)

<.0001

398 (100)

85 (24.4)

<.0001

0 (0)

93 (26.7)

<.0001

Normal LVFP

256 (73.6)

170 (48.9)

<.0001

Increased LVFP

90 (25.9)

83 (23.9)

NS

Grade I DD

256 (73.6)

0 (0)

<.0001

Grade II DD

87 (25.0)

80 (23.0)

NS

Grade III DD

3 (0.9)

3 (0.9)

NS

Cannot determine DD grade*

2 (0.6)

95 (27.3)

<.0001

DD Indeterminate DF*

Data are expressed as number (percentage). Bold text indicates statistical significance. *The 2009 recommendations do not take into account a specific category for patients not meeting the given criteria and in which assessment of DF and DD grade is not possible.

k = 0.43). In separate subanalyses, concordance was slightly, but not significantly, higher in patients with reduced LVEFs than in those with normal LVEFs (71.5% [k = 0.54] vs 64.0% [k = 0.38], P = .10). The overall DD reclassification rate was 35.3% (533 patients). One hundred fifty-nine patients (10.5%) were reclassified

from grade I DD to normal DF according to the 2016 recommendations, and 109 patients (7.2%) were reclassified from normal DF to grade I DD according to the 2016 recommendations (Table 5). In the overall population, 75 patients (5.0%) with grade II DD and 21 patients (1.4%) with not determinable DD grade according to

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Figure 1 Application of the first-step work flow of the 2016 recommendations to all patients with normal LVEFs, considering or not considering the presence of ‘‘myocardial disease.’’ Comparison of estimates of DD and LVFP between the correct application of the 2016 recommendations (i.e., considering myocardial disease; left) versus 2016 recommendations applying the firststep work flow to all patients with normal LVEFs (right, purple boxes). Not considering ‘‘myocardial disease’’ in the decision tree results in a significantly higher prevalence of patients with inconclusive diagnoses. Red arrows denote statistically significant differences of inconclusive diagnosis. the 2009 recommendations were reclassified to grade I DD with the 2016 version (Table 5). Among patients with reduced LVEFs, eight patients (6.2%) were reclassified from grade II DD to grade I DD on the basis of the 2016 algorithm (thus from elevated to normal LVFP), and 21 patients (16.1%) had indeterminate LVFP according to the 2009 recommendations but normal DF according to the 2016 update (data not shown). Figure 3 depicts a clinical example of reclassification from increased to normal LVFP (from grade II to grade I DD) in the setting of reduced LVEF. Table 6 shows demographic and echocardiographic characteristics of patients with normal and reduced LVEFs in whom the 2009 and 2016 recommendations assigned concordant and discordant grades of LVFP (normal vs increased LVFP). In both groups, patients who were reclassified from increased to normal LVFP with the 2016 recommendations had significantly lower E/e0 ratios, LAVi, and TR velocities compared with those in whom the two methods concordantly assigned increased LVFP.

DISCUSSION In the present study, we evaluated the clinical impact of the 2016 ASE/EACVI recommendations for the diagnosis and grading of DD and noninvasive estimation of LVFP, compared with the previous

Sorrentino et al 7

2009 version, in a population of outpatients referred for echocardiography at a generalist echocardiography laboratory. The application of the new recommendations highlighted the following: (1) a lower prevalence of DD and increased LVFP in the overall population, at the expense of a higher prevalence of inconclusive diagnosis of DF and of DD grade, compared with the 2009 recommendations; (2) a moderate overall concordance between the two recommendations for DD estimation; and, most important, (3) the impact of considering the presence of ‘‘myocardial disease’’ in the setting of patients with normal LVEF when applying the 2016 recommendations. Unlike the 2009 recommendations,15 the 2016 update14 suggests the use of multiple (three of four or two of three) parameters and proposes specific categories (‘‘indeterminate’’ DF and ‘‘cannot determine’’ DD grade) for patients whose data and characteristics render echocardiographic assessment unreliable. This evaluation avoids misleading noninvasive estimation of LVFP, probably reducing the falsepositive rate, thus increasing specificity, at the expense of a greater proportion of patients in whom a diagnosis is not achievable (reduced sensitivity).28 In the present study, the overall prevalence of DD and of abnormal LVFP was significantly lower by applying the 2016 version than the one obtainable by the 2009 recommendations. However, it must be considered that in an ambulatory setting, most patients have normal LVFP. We also found a higher rate of inconclusive diagnosis of DF and estimation of LVFP when using the 2016 recommendations. These findings are consistent with those of all the studies validating recommendations against catheterization laboratory data10-14 but only partially in agreement with other two investigations, which compared the prevalence of DD estimated using the two different approaches.18,19 In particular, Almeida et al.18 found an impressive difference of DD prevalence between the two recommendations, 38.1% (2009) versus 1.4% (2016), and a high prevalence of ‘‘indeterminate’’ DF (15.2%) in the new update. In our study, the difference in DD rate between the two recommendations was much lower (47.5% vs 36.1%), and we found a lower rate of ‘‘indeterminate’’ DF (7.3% vs 15.2%) than did Almeida et al. Notably, Almeida et al. enrolled only patients with normal LVEFs, whereas we included patients with both reduced and normal LVEFs, thus reporting a higher prevalence of DD. However, even limiting the analysis to the setting with normal LVEF, our DD prevalence was 42.6% (2009) versus 30.0% (2016), and most important, our rate of ‘‘indeterminate’’ DF was 8.0%. Notably, our separate subanalyses in patients with LVH, with CAD, and with valvular heart disease substantially confirmed the same results, showing an expected higher prevalence of grade I DD. In patients with LVH and with valvular heart disease, a lower prevalence of increased LVFP and thus a lower prevalence of grade II DD were observed when applying the 2016 recommendations in comparison with the 2009 recommendations. A key point of the new recommendations is related to the application of the concept of ‘‘myocardial disease.’’ We assigned ‘‘myocardial disease’’ when structural heart disease (i.e., LVH and significant valvular heart disease in accordance with Sato et al.’s14 validation) and/or CAD (i.e., in presence of regional wall motion abnormalities) were present. To the best of our knowledge, the present study is the first head-to-head comparison of the two recommendations assimilating patients with normal LVEFs and evidence of ‘‘myocardial disease’’ to patients with reduced LVEFs, as recommended by the 2016 version. The assumption of the presence of ‘‘myocardial disease’’ resulted in a lower rate of inconclusive diagnoses (‘‘indeterminate’’ DF as well as ‘‘cannot determine’’ DD grade). Accordingly, the lower prevalence of DD18,19 and the significantly higher rate of

8 Sorrentino et al

Journal of the American Society of Echocardiography - 2019

Figure 2 Sample of the impact of ‘‘myocardial disease’’ evaluation in the estimation of DF according to 2016 recommendations in a patient with normal LVEF. DF estimate without (purple box, right) and with (red box, left) consideration of ‘‘myocardial disease’’ (LVH) in a patient with normal LVEF. The consideration of LVH, as a marker of ‘‘myocardial disease,’’ changes the diagnosis of DF from assignment of ‘‘indeterminate’’ DF to grade I DD.

Table 5 Reclassification cross-relations for estimates of DD grading between 2009 and 2016 recommendations in the overall population 2016 recommendations Grading

Normal DF

Grade I DD

Grade II DD

Grade III DD

Cannot determine

Total

Normal DF

670

109

4

0

8

791

Grade I DD

159

137

13

0

36

345

Grade II DD

24

75

154

0

77

330

Grade III DD

0

0

0

13

0

13

Cannot determine*

1

21

6

0

1

29

854

342

177

13

122

1,508

2009 recommendations

Total

*The 2009 recommendations do not take into account a specific category for patients not meeting the given criteria and in which assessment of DD grade is not possible.

‘‘indeterminate’’ grade (15.2%)18 found by the two previous investigations may be attributed largely to the lack of application of the concept of ‘‘myocardial disease’’ to the 2016 recommendations (see Table 4). The concordance of DD grade assignment and LVFP estimation between the two recommendations was moderate in the present study, slightly but not significantly higher in patients with reduced LVEFs. The higher reclassification rate was found in patients who

were assigned DD or increased LVFP by using the 2009 recommendations and were redistributed to normal DF (159 patients) or normal LVFP (75 patients), respectively, according to the 2016 version. Notably, patients who were reclassified from increased to normal LVFP according to the 2016 recommendations had significantly lower TR velocity (see Table 6). The inclusion in the diagnostic algorithm of TR velocity, rather than PASP, seems therefore to further reduce the rate of estimated increased LVFP. Pulmonary

Sorrentino et al 9

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Figure 3 Comparison of LVFP estimate according to the 2009 (blue, left) and 2016 (red, right) recommendations in a patient with reduced LVEF. According to the 2009 recommendations, in the presence of reduced E/A ratio < 1, E velocity > 50 cm/sec, E/e0 ratio between 9 and 13, and PASP > 35 mm Hg, the patient was assigned increased LVFP. Conversely, according to 2016 recommendations, in the presence of only one of the three suggested parameters reaching the cutoff for abnormal (LAVi), the patient was reclassified as normal LVFP.

Table 6 Characteristics of patients with normal LVEFs ($53%) and reduced LVEFs (<53%) in which the 2009 and 2016 recommendations were discordant (reclassification from increased to normal LVFP) and concordant (no reclassification) in the estimation of LVFP Normal LVEF ($53%)

Reduced LVEF (<53%)

Concordant n = 130 (9.4%) Increased / increased LVFP

Discordant n = 8 (6.2%) Increased / normal LVFP

Concordant n = 37 (28.5%) Increased / increased LVFP

Variable

Discordant n = 91 (6.6%) Increased / normal LVFP

65.9 6 11.3

69.4 6 10.9

.02

68.0 6 8.8

69.5 6 10.0

.666

Systolic BP, mm Hg

133.2 6 18.4

139.2 6 19.3

.02

141.2 6 18.0

132.0 6 17.8

.219

Age, y

P

P

Diastolic BP, mm Hg

77.7 6 8.8

78.1 6 10.7

.746

81.2 6 12.1

77.0 6 11.0

.388

Heart rate, beats/min

67.8 6 10.4

69.3 6 10.7

.334

68.1 6 7.8

69.5 6 9.8

.674

E/e0 ratio

12.3 6 8.2

14.2 6 3.5

.01

11.6 6 4.4

17.9 6 6.6

.005

Septal e0 , cm/sec

6.3 6 1.7

5.8 6 1.6

.06

4.1 6 1.1

4.3 6 1.5

.675

Lateral e0 , cm/sec

8.3 6 2.3

7.0 6 2.0

<.0001

5.1 6 2.1

5.9 6 2.5

.378

33.9 6 8.3

41.5 6 9.6

<.0001

31.1 6 8.1

48.1 6 15.0

<.0001

2.5 6 0.3

2.9 6 0.3

<.0001

2.6 6 0.2

2.8 6 0.4

.03

2

LAVi, mL/m

TR velocity, m/sec

BP, Blood pressure. Data are expressed as mean 6 SD. Bold text indicates statistical significance.

hypertension has shown to distinguish heart failure with normal LVEF from hypertensive cardiomyopathy with high accuracy, with an incremental diagnostic and prognostic value on other Doppler indices of DD.29

Notably, we decided to exclude from the analysis patients with atrial fibrillation, cardiomyopathies, severe aortic and/or mitral regurgitation, and mitral stenosis and those who underwent mitral and/or aortic valve surgery or aortic valve transcatheter replacement.

10 Sorrentino et al

Although both the 200916 and 201615 recommendations provide additional parameters and/or different cutoff points in these clinical settings to achieve an appropriate diagnosis, they do not provide specific algorithms for the estimation of LVFP under these circumstances.

Study Limitations The main limitation corresponds to the lack of invasive assessments, which hinders the evaluation of the accuracy of our findings versus cardiac catheterization. Large studies have already proved the significant improvement of the 2016 recommendations in the noninvasive estimation of LVFP.11-14 Their results are consistent with the lower prevalence of increased LVFP found in the present study. The lack of acquisition of IVRT, Valsalva maneuver changes of transmitral E velocity, and Doppler-derived pulmonary venous flow velocities, in particular Ar-A difference, considered in both the 2009 and 2016 recommendations, is another major limitation. The determination of these parameters appears to be additionally useful in specific cardiac diseases, such as atrial fibrillation, cardiomyopathies (which were excluded from the present study), and valvular heart disease (which was partially excluded). The rate of indeterminant DF may be expected to be lower in echocardiography laboratories routinely applying these measurements. However, the Valsalva maneuver and pulmonary venous flow velocities have recognized low feasibility (61% and 73%, respectively).10 This was substantially confirmed in a subanalysis of our study (72% and 70%, respectively, among 50 patients). In particular, the reduced feasibility of Valsalva changes in mitral E velocity is due mainly to a failure of obtaining an adequate trace recording, in relation with the patient’s inability to understand instructions.30 In addition, we also found suboptimal interstudy reproducibility of IVRT, which was reported as moderate in two previous studies.26,27 The application of IVRT/TE-e0 ratio and E velocity/ velocity flow propagation ratio, taken into account in the 2009 recommendations in patients with E/A ratios > 1 to <2, is now limited to specific settings in which other parameters are not reliable. Another limitation might be the relatively low percentage of patients with heart failure and CAD with reduced LVEFs in our population. This could have been at least partially expected in a general echocardiography laboratory such as ours. However, the absolute number of patients with CAD and/or low LVEFs was sufficient to allow subanalyses, substantially confirming the results also in these clinical subsettings. In general, our population included patients with a large spectrum of cardiac diseases, a variety of cardiovascular risk factors, and even a large number of oncology patients, examined for standardized protocols or symptom worsening. This represents an advantage compared with other studies that included only patients referred for cardiac catheterization and/or patients with normal LVEFs.

Clinical Implications This work highlights the critical role of the physician in the application of the DF recommendations, as they should be based on a general and comprehensive echocardiographic assessment combining the available echocardiographic data with patients’ clinical information. Nevertheless, the higher prevalence of patients in whom DD diagnosis is not achievable does not necessarily represent a limitation but, in the presence of overt symptoms and reasonable clinical suspicion, should be a starting point for further diagnostic testing, such as stress echocardiography,31,32 advanced echocardiographic technologies (left atrial strain),33 or even cardiac catheterization.34

Journal of the American Society of Echocardiography - 2019

CONCLUSION The present study confirms the previously observed lower prevalence of DD and increased LVFP and the higher rate of inconclusive diagnoses assessed with the 2016 recommendations, compared with the 2009 version. Moreover, it represents the first comparison of the two recommendations assimilating patients with normal LVEFs and evidence of ‘‘myocardial disease’’ to patients with reduced LVEFs, as recommended in the 2016 update. When applying the 2016 recommendations, the incorporation of ‘‘myocardial disease’’ resulted in a higher prevalence of DD and a lower prevalence of inconclusive diagnosis.

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