Echocardiographic Evaluation of Left Ventricular Output in Patients with Heart Failure: A Per-Beat or Per-Minute Approach?

Echocardiographic Evaluation of Left Ventricular Output in Patients with Heart Failure: A Per-Beat or Per-Minute Approach? Donato Mele, MD, Gabriele Pestelli, MD, Davide Dal Molin, MD, Filippo Trevisan, MD, Vittorio Smarrazzo, MD, Giovanni Andrea Luisi, MD, Alessandro Fucili, MD, and Roberto Ferrari, MD, Cona and Cotignola, Italy

Background: Left ventricular (LV) output is a predictor of adverse outcome in patients with heart failure. It can be evaluated using a per-beat approach, measuring stroke volume index (SVI), or a per-minute approach, calculating cardiac index (CI). However, the prognostic value of these two approaches has never been compared. Methods: A single-center retrospective observational study was conducted in 396 hospitalized patients who underwent echocardiography for suspected heart failure. In a group of 138 consecutive patients, SVI and CI cutoff values of 30 mL/m2 and 2.3 L/min/m2, respectively, were derived to separate normal from low LV forward flow conditions. Subsequently, the association of these values with all-cause mortality was compared in a group of 258 consecutive patients. Median follow-up duration was 2.6 years (interquartile range: 2-3.2 years). Results: After adjustment for other outcome predictors, SVI <30 mL/m2 was independently associated with allcause mortality with a hazard ratio of 2.67 (95% confidence interval, 1.74-4.1; P < .001), whereas CI was not. Additionally, three different subgroups of SVI (<30, 30-35, and >35 mL/m2) and CI (<1.8, 1.8-2.2, and $2.3 L/ min/m2) were compared, and no incremental benefit of this risk stratification model was observed. Conclusions: Low LV output on the basis of a per-beat definition (SVI <30 mL/m2) is strongly associated with all-cause mortality in patients hospitalized with heart failure. A per-minute approach seems to add no further information to risk stratification. These findings may have implications for selecting the LV output index when evaluating prognosis in patients with heart failure. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Heart failure, Echocardiography, Left ventricular function, Stroke volume, Hemodynamics

Measurement of left ventricular (LV) output in patients with heart failure (HF) is a fundamental evaluation. LVoutput can be assessed using a per-beat measure, such as the stroke volume index (SVI), or a perminute measure, such as the cardiac index (CI). Although both SVI and CI are representative of LV systolic function, it is still unclear whether they differ in their capability to predict prognosis in patients with HF. LV output can be assessed using cardiac catheterization and echocardiography. Cardiac catheterization is the reference standard, but it is an invasive procedure and cannot be applied extensively in clinical practice. Conversely, echocardiography has the potential to be applied virtually to all patients with HF, and several studies have shown that it agrees with cardiac catheterization for assessment of

From the Cardiology Unit and LTTA Centre, University of Ferrara, Ferrara (D.M., G.P., D.D.M., F.T., V.S., G.A.L., A.F., R.F.) and Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola (R.F.), Italy. Conflicts of Interest: None. Reprint requests: Donato Mele, MD, Cardiology Unit, University Hospital of Ferrara, Viale Aldo Moro 8, 44024 Cona, Ferrara, Italy (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.09.009

cardiac output in the setting of HF.1-4 In this study, we used echocardiography to define whether SVI or CI is the most relevant evaluation associated with HF prognosis. We also sought to determine the impact of different cutoff values of SVI and CI on the association with outcome.

METHODS Population This investigation included 396 hospitalized patients who underwent echocardiography for suspected HF. The study was conducted in two consecutive groups of patients. The first group was used to derive SVI and CI cutoff values separating patients with normal and low LV forward flow (derivation study). The second group was used to evaluate the prognostic impact of SVI and CI (validation study). All echocardiograms were obtained in the central echocardiographic laboratory of our hospital. Derivation Group An initial population of 194 consecutive adult patients admitted to our hospital from January to June 2014 who underwent 1

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Abbreviations

ACE = Angiotensinconverting enzyme

ARB = Angiotensin receptor blocker

CI = Cardiac index HF = Heart failure HR = Hazard ratio LV = Left ventricular LVEF = Left ventricular ejection fraction

LVOT = Left ventricular outflow tract

RV = Right ventricular SV = Stroke volume SVI = Stroke volume index TAPSE = Tricuspid annular plane systolic excursion

Journal of the American Society of Echocardiography - 2019

echocardiography for suspected HF during hospitalization was evaluated. At hospital discharge, 152 patients had confirmed diagnoses of HF and were considered for the study. At the moment of the echocardiographic analysis, 14 patients were excluded because of severe valve heart disease, defined on the basis of current guidelines,5,6 and inadequate image quality, defined as unclear visualization of the LV outflow tract (LVOT) from the parasternal window or the LV endocardial border in more than two myocardial segments from the apical window. No patient had subaortic acceleration such as hypertrophic obstructive cardiomyopathy or intracardiac shunt flow. Thus, the final study population included 138 patients.

Validation Group We evaluated an initial population of 320 consecutive adult patients admitted to our hospital who underwent echocardiography for suspected HF during a 1-year period (from June 2014 to June 2015). At hospital discharge, 287 patients had confirmed diagnoses of HF and were considered for the study (among those not confirmed as having HF, 13 patients had pulmonary embolism, nine had acute coronary syndrome, eight had pneumonia and sepsis, and three had chronic obstructive pulmonary disease exacerbation). At the time of the echocardiographic analysis, 29 patients were excluded because of obstructive hypertrophic cardiomyopathy (n = 2), severe valve heart disease (n = 13), and inadequate image quality as defined above (n = 12). No patient had intracardiac shunt flow. Two patients were lost to follow-up. Thus, the final population included 258 patients. One hundred eight patients (42%) were admitted to the emergency department (including intensive care units and emergency medicine, cardiology, and pneumology units) and 150 patients (58%) to the medicine department (including medicine and geriatrics units). Demographic and Clinical Data Baseline demographic and clinical characteristics and therapy at baseline and discharge were collected. Hypertension was defined on the basis of the use of antihypertensive drugs or a previous diagnosis of hypertension. The first blood pressure measurement at the time of admission was used. Heart rate and rhythm at the time of the echocardiographic examination were recorded. Echocardiographic Examination A comprehensive two-dimensional echocardiographic, Doppler, and color Doppler examination was performed using a GE Vivid 7 or E9 echocardiographic scanner (GE Healthcare, Milwaukee, WI) equipped with a 3.5-MHz transducer. Echocardiographic images were stored in digital format and were retrieved for analysis using

EchoPAC version 201 (GE Healthcare). One trained physician performed all echocardiographic measures, in accordance with American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines.7 For interobserver variability, a second trained physician blindly repeated the necessary measures using the same criteria.7 LV end-diastolic and end-systolic volumes were calculated from orthogonal apical views using the biplane Simpson method. LV ejection fraction (LVEF) was derived from the standard equation after calculation of global stroke volume (SV).8 Valve regurgitations and stenoses were graded according to recent guidelines.5,6 To estimate LV filling pressure, the validated algorithm of current recommendations for the evaluation of LV diastolic function was used.9,10 According to this algorithm, first the mitral inflow pattern was used to differentiate LV filling pressure status, with E/A ratio #0.8 and E wave #50 cm/sec indicating normal LV filling pressure and E/A ratio $2 indicating increased LV filling pressure. Then, in patients with intermediate mitral inflow pattern (E/A ratio #0.8 and E wave >50 cm/sec or E/A ratio >0.8 to <2), the combination of E/e’ ratio, left atrial maximal volume index, and peak tricuspid regurgitant velocity was used to estimate LV filling pressure.9,10 Right ventricular (RV) function was measured using tricuspid annular plane systolic excursion (TAPSE) on the M-mode trace.7 For each Dopplerbased and M-mode measurement, estimates were the averages of three cardiac cycles in sinus rhythm and five in atrial fibrillation. LV forward SV was calculated as the product of the LVOT area and the time-velocity integral of aortic flow velocity (also known as stroke distance) recorded in the apical five-chamber or long-axis view. LVOT area was calculated as p (LVOT diameter/2)2. The diameter of the LVOT was measured in the parasternal long-axis view.11,12 The LVOT time-velocity integral was assessed using pulsed-wave Doppler, with the sample volume positioned in the middle of the LVOT below the aortic cusps. Cardiac output was calculated multiplying LV SV by heart rate. Because both SV and cardiac output depend on body surface area, they were indexed to body surface area (in square meters) to obtain SVI and CI, respectively. Body surface area was obtained using the Mosteller formula.13 Endpoints and Follow-Up Duration Derivation Study. The study end point was mortality for any cause. The median duration of the follow-up period was 2.3 years (interquartile range: 1.7-3.1 years). Validation Study. The study end point for the primary objective was mortality from any cause and, for the secondary objective, the combination of mortality from any cause and HF rehospitalization at 6 months. For both objectives, SVI and CI cutoff values obtained from the derivation study were used to discriminate outcomes. For the primary objective, the impact of the following factors on outcome was evaluated: b-blocker therapy at admission, echocardiography performed within and after 3 days from hospitalization, and LVEF. To explore the effect of heart rate at the moment of echocardiography and better understand possible discrepancies between SVI and CI, four hemodynamic subgroups were defined, combining the two LV output indices: low SVI, low CI; low SVI, normal CI; normal SVI, low CI; and normal SVI, normal CI. Finally, two additional SVI and CI cutoff values from the literature, 35 mL/m2 for SVI5 and 1.8 L/ min/m2 for CI,14,15 were used to compare three subgroups of patients for each variable: <30, 30 to 35, and >35 mL/m2 for SVI and <1.8, 1.8 to 2.2, and $2.3 L/min/m2 for CI. The median duration of the follow-up period was 2.6 years (interquartile range: 2-3.2 years). For both the derivation and validation investigations, vital status was

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HIGHLIGHTS  Assessment of left ventricular (LV) output is important in heart failure patients.  LV output can be measured by both stroke volume index (SVI) and cardiac index (CI).  SVI is better associated with outcome than CI in hospitalized heart failure patients. determined by the hospital medical informatics platform. The study was approved by the local ethics committee. Statistical Analysis Derivation Group. Nonparametric distribution was tested using the Kolmogorov-Smirnov test. Continuous variables are expressed as median (interquartile range). Categorical variables are reported as count (percentage). Receiver operating characteristic curve analysis was used to determine the optimal SVI and CI cutoff values. The area under the curve was calculated. Validation Group. Descriptive statistical methods were the same as in the derivation study. Differences between groups were tested using the Mann-Whitney U test for continuous variables and the c2 test or Fisher exact test for categorical variables, as appropriate. Estimated survival rates and 95% confidence intervals were obtained using the Kaplan-Meier method and compared using the log-rank test. To evaluate the effects of covariates, a Cox univariate analysis was initially performed. Then an age-adjusted Cox univariate analysis was used to identify variables significantly associated with outcome. These variables were included in a multivariate Cox model, and the hazard ratio (HR) of each variable was calculated. SVI and CI values and LV global and forward SV values were correlated using the Spearman correlation coefficient, r, used because of the skewed data distribution. Observer Variability. The intra- and interobserver variability for the SVI measure was assessed in a random sample of 26 patients (10%) from the validation group. It was defined as the SD of the differences between measures and expressed as a percentage of the mean value of the first observer. Data were analyzed using IBM SPSS Statistics version 24. Differences were considered statistically significant at P < .05. RESULTS Derivation Group Patients’ characteristics are reported in Table 1. The median time for the echocardiographic study was 3 days (interquartile range: 26 days). In receiver operating characteristic curve analysis, both SVI and CI discriminated outcome (areas under the curve, 0.68 [P < .001] and 0.66 [P = .001], respectively; Figure 1). The optimal cutoff values were 30 mL/m2 for SVI (sensitivity, 66%; specificity, 70%) and 2.3 L/min/m2 for CI (sensitivity, 66%; specificity, 60%; Figure 1). Validation Group Patient characteristics in the overall population and in subgroups with normal and reduced SVI and CI (defined according to the cutoff values obtained in the derivation study) are reported in Table 2. A wide spectrum of severity characterized HF in this patient population.

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The median time for the echocardiographic study was 3 days (interquartile range: 1-7 days). Sixty-nine patients were examined within the first 24 hours. At the moment of the echocardiographic examination, patients with lower SVI had higher heart rate and a higher prevalence of atrial fibrillation and LVEF <50% compared with patients with normal SVI (Table 2). LV filling pressure was increased in the majority of patients in all subgroups, with a higher prevalence in subgroups with lower SVI and CI (Table 2). Regarding the primary objective, Figure 2 shows the Kaplan-Meier curves indicating survival according to SVI (Figure 2A) and CI (Figure 2B) cutoff values determined in the derivation study. Both indices differentiated patients with different outcomes, although SVI did so at a high level of statistical significance. Results of the Cox univariate and multivariate analysis are reported in Table 3. In univariate analysis adjusted for age, male sex, systolic blood pressure, history of HF, elevated natriuretic peptides, chronic kidney disease, TAPSE, SVI <30 mL/m2, and CI <2.3 L/min/m2 were directly associated with mortality, whereas the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) at discharge was inversely associated (Table 3). In multivariate analysis, age, male sex, history of HF, chronic kidney disease, use of ACE inhibitors or ARBs, and SVI remained significantly associated with mortality (Table 3). Table 4 reports results of Cox regression analysis with relative risk for all-cause mortality according to b-blocker treatment at admission, timing of echocardiography, and LVEF. In the multivariate analysis, only SVI was significantly associated with mortality both in patients with and in those without b-blocker therapy at presentation and in those examined within and after 3 days from hospitalization. In the subgroup of patients examined using echocardiography within 24 hours, in univariate age-adjusted Cox analysis, SVI was associated with outcome (HR, 2.24; 95% confidence interval, 1.01-4.96; P = .046), while CI was not (HR, 2.09; 95% confidence interval, 0.97-4.53; P = .062). In patients with LVEFs $50%, the multivariate Cox analysis revealed that SVI, not CI, was associated with outcome (Table 4). In patients with LVEFs <50%, SVI was associated with outcome in the univariate age-adjusted Cox analysis, whereas CI was not (Table 4). In these patients, after adjustment for significant parameters excluding TAPSE (age, male sex, systolic blood pressure, history of HF, ischemic etiology, chronic kidney disease, use of ACE inhibitors or ARBs, and coronary artery disease), in the multivariate analysis, SVI was still independently associated with outcome (HR, 1.9; 95% confidence interval, 1.14-3.18; P = .014). However, when TAPSE was added to the Cox regression model, only age (per 5 years: HR, 1.3; 95% confidence interval, 1.12-1.5; P = .001), chronic kidney disease (HR, 3.38; 95% confidence interval, 1.88-6.09; P < .001), and TAPSE (per 1-mm increase: HR, 0.9; 95% confidence interval, 0.83 to 0.97; P = .006) remained significantly associated with outcome. No significant association was found for CI in multivariate Cox analysis in patients with reduced LVEFs. Figure 3 shows the Kaplan-Meier curves of the four hemodynamic subgroups defined using the SVI and CI cutoff values. Patients with low SVI and low CI had worse outcomes compared with those with normal SVI and normal CI (P = .001). Patients with reduced CI only did not differ from those with normal SVI and CI (P = .771) and those with reduced SVI only (P = .075) but had better outcomes than those with low SVI and low CI (P = .014). This signifies that the addition of SVI in patients with reduced CI further stratifies prognosis. Patients with reduced SVI only had worse outcomes than those with normal SVI and normal CI (P = .048) but did not differ from those with reduced SVI and CI (P = .764). This highlights

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Table 1 Baseline characteristics of the derivation study population Patients, N

138

Age, y

79 (72-86)

Sex, male

64 (46)

BMI, kg/m2 BSA, m2

27 (24-31) 1.86 (1.71-2.01)

History of HF

36 (26)

History of AF

68 (49)

Ischemic etiology

43 (31)

Hypertension

104 (75)

Diabetes

34 (25)

CKD

42 (30)

CAD

54 (39)

COPD

34 (25)

MRA at discharge Duration of hospitalization, days Death at follow-up

49 (36) 9 (6-14) 62 (45)

ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; LVEDVI, LV end-diastolic volume index; LVESVI, LV end-systolic volume index; LVMI, LV mass index; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography. Continuous variables are expressed as median (interquartile range) and categorical variables as count (percentage).

NYHA functional class II

5 (4)

III

121 (88)

IV

12 (9)

High NPs

71 (51)

SBP at admission, mm Hg DBP at admission, mm Hg

140 (120-160) 80 (70-90)

Creatinine at admission, mg/dL

1.22 (0.91-1.69)

HR at admission, beats/min

100 (81-117)

Bradycardia (HR <60 beats/min) at admission Tachycardia (HR >100 beats/min) at admission Intravenous diuretics at admission

5 (4) 62 (45) 112 (81)

TTE within 3 days

73 (53)

HR during TTE, (beats/min)

75 (65-86)

Bradycardia (HR <60 beats/min) during TTE

17 (12)

Tachycardia (HR >100 beats/min) during TTE

14 (10)

AF during TTE

60 (44)

2

LVMI, g/m

Figure 1 Receiving operating characteristic analysis for determination of the best SVI and CI in the derivation study group. AUC, Area under the curve.

106 (93-127)

LVEDVI, mL/m2

57 (45-74)

LVESVI, mL/m2

28 (19-48)

LVEF, %

50 (35-60)

LVEF <50%

72 (52)

TAPSE, cm

1.8 (1.5-2.1)

SVI, mL/m2

31 (25-39)

CI, L/min/m2

2.4 (1.9-2.8)

Increased LV filling pressure

107 (78)

Moderate MR

65 (47)

Moderate AR

13 (9)

Moderate TR

29 (21)

b-blocker at admission

63 (46)

ACE inhibitor/ARB at admission

75 (54)

MRA at admission

25 (18)

b-blocker at discharge

94 (69)

ACE inhibitor/ARB at discharge

60 (44)

that the addition of CI in patients with reduced SVI does not help to further stratify prognosis. Patient characteristics in the four hemodynamic subgroups are reported in Supplemental Table 1. Compared with patients with normal SVI and low CI, those with low SVI and normal CI had lower systolic blood pressure, had higher heart rates at admission and during echocardiography, were less often on b-blocker therapy at admission, and had lower LVEFs. Figure 4 shows the Kaplan-Meier curves of additional SVI and CI cutoff values. Dividing patients with SVI $30 mL/m2 into two subgroups (30-35 and >35 mL/m2) did not improve outcome stratification (Figure 4A), as well as dividing patients with CI <2.3 L/min/m2 into two subgroups (1.8-2.2 and <1.8 L/min/m2; Figure 4B). Table 5 reports the results of the Cox regression analysis with the relative risk for all-cause mortality according to the additional SVI and CI cutoff values. Although in the univariate analysis, SVI <30 mL/m2 and CI <1.8 L/min/m2 were significantly associated with outcome, in the multivariate analysis, only SVI remained significantly associated with mortality.

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Table 2 Baseline characteristics of the validation study population Total (N = 258)

Age, y Sex, male BMI, kg/m2 BSA, m2

78 (70-85) 135 (52) 27 (24-30) 1.85 (1.68-1.97)

SVI <30 mL/m2 (n = 89 [35%])

SVI $30 mL/m2 (n = 169 [65%])

P

CI <2.3 L/min/m2 (n = 101 [39%])

CI $2.3 L/min/m2 (n = 157 [61%])

P

77 (68-85)

80 (70-85)

.268

77 (68-85)

80 (71-85)

48 (54)

87 (52)

.708

59 (58)

76 (48)

.116

27 (24-29)

27 (24-30)

.879

27 (24-29)

26 (24-30)

.813

.129

1.89 (1.7-2.01)

1.89 (1.70-1.98)

1.83 (1.67-1.97)

.224

1.83 (1.66-1.96)

.071

History of HF

68 (26)

25 (28)

43 (25)

.647

29 (29)

39 (25)

History of AF

95 (37)

37 (42)

58 (34)

.251

44 (44)

51 (33)

.072

Ischemic etiology

77 (30)

28 (32)

49 (29)

.681

35 (35)

42 (27)

.176

Hypertension

.491

185 (72)

58 (65)

127 (75)

.091

64 (63)

121 (77)

.017

Diabetes

74 (29)

22 (25)

52 (31)

.307

26 (26)

48 (31)

.402

CKD

83 (32)

29 (33)

54 (32)

.918

32 (32)

51 (33)

.893

CAD

101 (39)

38 (43)

63 (37)

.397

44 (44)

57 (36)

.244

43 (17)

12 (14)

31 (18)

.319

13 (13)

30 (19)

.19

COPD NYHA functional class

.157

.134

II

22 (9)

11 (12)

11 (7)

13 (13)

9 (6)

III

214 (82)

73 (82)

141 (83)

80 (79)

134 (85)

22 (9)

5 (6)

17 (10)

High NPs

IV

126 (49)

46 (52)

80 (47)

SBP at admission, mm Hg

140 (120-160)

130 (110-150)

150 (130-170)

DBP at admission, mm Hg

80 (70-90)

80 (70-100)

80 (70-90)

Creatinine at admission, mg/dL HR at admission, beats/ min Bradycardia (HR <60 beats/min) at admission

1.19 (0.95-1.74) 90 (78-110)

1.19 (0.96-1.70) 100 (85-130)

.507 <.001

8 (8)

14 (9)

52 (52)

74 (47)

.495

140 (120-160)

145 (130-160)

.07

.824

80 (70-95)

80 (70-90)

.508

1.18 (0.95-1.74)

.595

1.18 (0.96-1.7)

1.2 (0.93-1.76)

.736

90 (76-100)

.004

92 (75-130)

90 (80-107)

.691

5 (2)

1 (1)

4 (2)

.491

3 (3)

2 (1)

.335

Tachycardia (HR >100 beats/min) at admission

49 (19)

26 (29)

23 (14)

.002

25 (25)

24 (15)

.058

Intravenous diuretics at admission

197 (76)

70 (79)

127 (75)

.529

77 (76)

120 (76)

.971

TTE within 3 days

130 (50)

48 (54)

82 (49)

81 (69-96)

71 (63-79)

.409

HR during TTE, beats/ min

74 (64-84)

Bradycardia (HR <60 beats/min) during TTE

34 (13)

5 (6)

29 (17)

Tachycardia (HR >100 beats/min) during TTE

23 (9)

18 (20)

5 (3)

<.001

33 (20)

<.001

AF during TTE LVMI, g/m2

75 (29)

42 (47)

<.001 .009

51 (51)

79 (50)

.978

69 (60-82)

75 (67-85)

.006

21 (21)

13 (8)

.004

7 (7)

16 (10)

.370

32 (20)

<.001

43 (43)

112 (95-135)

110 (94-139)

113 (96-133)

.779

113 (95-138)

112 (95-133)

.881

LVEDVI, mL/m2

63 (49-82)

67 (44-88)

63 (51-80)

.949

62 (47-90)

64 (50-79)

.635

LVESVI, mL/m2

31 (21-53)

40 (21-63)

29 (21-48)

.038

37 (22-65)

29 (20-48)

.026

LVEF, %

48 (32-57)

33 (28-55)

51 (39-58)

<.001

38 (29-55)

51 (39-59)

<.001

LVEF <50%

136 (53)

62 (70)

74 (44)

<.001

66 (65)

70 (45)

TAPSE, cm

1.8 (1.5-2)

1.4 (1.2-1.8)

1.9 (1.7-2.1)

<.001

1.5 (1.3-1.8)

1.9 (1.7-2.1)

.001 <.001

SVI, mL/m2

33 (26-42)

24 (21-26)

39 (33-46)

<.001

25 (21-31)

39 (32-46)

<.001

CI, L/min/m2

2.5 (2-3.1)

1.9 (1.6-2.2)

2.8 (2.4-3.4)

<.001

1.9 (1.6-2.1)

2.9 (2.6-3.5)

<.001 (Continued )

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Journal of the American Society of Echocardiography - 2019

Table 2 (Continued ) Total (N = 258)

SVI <30 mL/m2 (n = 89 [35%])

SVI $30 mL/m2 (n = 169 [65%])

P

CI <2.3 L/min/m2 (n = 101 [39%])

CI $2.3 L/min/m2 (n = 157 [61%])

P

Increased LV filling pressure

154 (60)

56 (63)

98 (58)

.035

68 (67)

86 (55)

.005

Moderate MR

134 (52)

61 (69)

73 (43)

<.001

61 (60)

73 (47)

.029

Moderate AR

24 (9)

6 (7)

18 (11)

.304

9 (9)

15 (10)

.862

Moderate TR

71 (28)

32 (36)

39 (23)

.026

31 (31)

40 (26)

.350

b-blocker at admission

123 (48)

33 (37)

90 (53)

.013

46 (46)

77 (49)

.583

ACE inhibitor/ARB at admission

133 (52)

36 (40)

97 (57)

.01

42 (42)

91 (58)

.01

MRA at admission

47 (18)

22 (25)

25 (15)

.05

26 (26)

21 (13)

.012

b-blocker at discharge

193 (77)

66 (76)

127 (77)

.778

77 (78)

116 (76)

.788

ACE inhibitor/ARB at discharge

129 (51)

41 (47)

88 (54)

.324

49 (50)

80 (53)

.627

MRA at discharge

122 (49)

43 (49)

79 (48)

.85

51 (52)

71 (47)

.457

Duration of hospitalization, days Death at follow-up HF at 6 months Composite end point

9 (5-14) 107 (42)

9 (6-14) 50 (56)

8 (5-14) 57 (34)

.885 .001

8 (6-14) 50 (50)

9 (5-15) 57 (36)

.543 .036

44 (17)

19 (21)

25 (15)

.183

18 (18)

26 (17)

.793

122 (47)

54 (61)

68 (40)

.002

55 (55)

67 (43)

.064

ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; LVEDVI, LV end-diastolic volume index; LVESVI, LV end-systolic volume index; LVMI, LV mass index; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography. Continuous variables are expressed as median (interquartile range) and categorical variables as count (percentages).

Figure 2 Kaplan-Meier survival curves according to SVI (A) and CI (B) cutoff values obtained in the derivation study.

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Table 3 Cox regression analysis with relative risk for all-cause mortality Univariate HR (95% confidence interval)

P

Age (per 5 y)

1.24 (1.12-1.37)

<.001

Sex, male

1.39 (0.94-2.04)

.096

1.69 (1.14-2.50)

.009

BMI

1.01 (0.98-1.05)

.461

1.03 (0.99-1.07)

.105

HR at admission

1.00 (1-1.01)

.356

1.01 (1-1.01)

.282

HR during TTE

1.00 (0.99-1.01)

.924

1.01 (0.99-1.02)

.385

SBP at admission

0.99 (0.98-1.00)

.009

1.05 (1.03-1.08)

.004

NYHA functional class

Age-adjusted univariate HR (95% confidence interval)

.901

P

P

1.32 (1.18-1.48)

<.001

1.81 (1.16-2.83)

.009

.165

.793

AF during TTE

1.53 (1.03-2.27)

.035

1.44 (0.97-2.13)

.073

High NPs

1.49 (1.02-2.18)

.041

1.41 (0.96-2.07)

<.001

History of HF

1.69 (1.14-2.51)

.009

1.59 (1.07-2.36)

.023

Ischemic etiology

Multivariate HR (95% confidence interval)

1.4 (0.95-2.08)

.093

1.41 (0.95-2.1)

.086

History of AF

1.39 (0.95-2.03)

.094

1.29 (0.88-1.90)

.190

Hypertension

1.39 (0.89-2.17)

.151

1.11 (0.71-1.76)

.644

Diabetes

1.15 (0.77-1.72)

.496

1.31 (0.87-1.98)

.204

CKD

2.37 (1.62-3.48)

<.001

2.16 (1.47-3.17)

<.001

CAD

1.43 (0.98-2.09)

.067

1.45 (0.99-2.11)

.058

COPD

1.52 (0.96-2.41)

.077

1.42 (0.89-2.25)

.140

b-blocker at discharge

0.79 (0.51-1.23)

.290

0.84 (0.54-1.31)

.450

ACE inhibitor/ARB at discharge

0.36 (0.24-0.54)

<.001

0.36 (0.24-0.54)

<.001

MRA at discharge

0.88 (0.60-1.30)

.53

0.95 (0.65-1.41)

.815

LVEF

1.40 (0.38-5.24)

.615

0.71 (0.18-2.81)

.624

LVEF <50%

0.98 (0.67-1.42)

.894

1.16 (0.79-1.71)

.446

LVEDVI

1.00 (0.99-1.01)

.539

1.00 (1.00-1.01)

.436

LVMI

1.00 (0.99-1.01)

.765

1.00 (0.99-1.01)

.87

Moderate MR

0.98 (0.67-1.42)

.895

1.06 (0.72-1.55)

.772

Moderate AR

1.38 (0.76-2.52)

.291

1.21 (0.66-2.21)

.539

Moderate TR

1.45 (0.97-2.17)

.068

1.42 (0.95-2.12)

.089

Increased LV filling pressure

1.32 (0.8-2.17)

.275

1.36 (0.83-2.24)

.226

TAPSE (per 1-mm increase)

0.93 (0.88-0.97)

.002

0.92 (0.87-0.97)

.001

SVI <30 mL/m2

2.09 (1.43-3.05)

<.001

2.52 (1.71-3.71)

<.001

CI <2.3 L/min/m2

1.56 (1.07-2.28)

.022

1.81 (1.23-2.66)

.002

.71 1.94 (1.25-3.01)

.003

.052

0.44 (0.28-0.69)

<.001

.59 2.54 (1.64-3.92)

<.001 .829

ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; LVEDVI, LV end-diastolic volume index; LVMI, LV mass index; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography.

Regarding the secondary objective, in the univariate analysis adjusted for age, male sex, systolic blood pressure, atrial fibrillation during echocardiography, history of HF, elevated natriuretic peptides, chronic kidney disease, chronic obstructive pulmonary disease, TAPSE, SVI <30 mL/m2, and CI <2.3 L/min/m2 were directly associated with the combined endpoint of all-cause mortality and HF rehospitalization at 6 months, whereas use of ACE inhibitors or ARBs at discharge was inversely associated

(Supplemental Table 2). In the multivariate analysis, age, male sex, history of HF, chronic kidney disease, use of ACE inhibitors or ARBs and SVI were significantly associated with outcome (Supplemental Table 2). A significant correlation was found between SVI and CI (r = 0.792, P < .001; Figure 5) and between LV global and forward SV (r = 0.536, P < .001). Intraobserver and interobserver variability in measuring SVI were 1.4 mL/m2 (5%) and 1.6 mL/m2 (6%), respectively.

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Table 4 Cox regression analysis with relative risk for all-cause mortality according to b-blocker therapy at admission, timing of TTE, and LVEF subgroups Univariate HR (95% confidence interval)

P

Age-adjusted univariate HR (95% confidence interval)

P

Multivariate HR (95% confidence interval)

P

No BB therapy at admission (n = 135) SVI <30 mL/m2

1.56 (0.9-2.7)

.113

2.35 (1.32-4.18)

.004

CI <2.3 L/min/m2

1.11 (0.64-1.92)

.725

1.48 (0.83-2.63)

.184

2.15 (1.15-4.04)

.017

4.09 (2.21-7.59)

<.001

BB therapy at admission (n = 123) SVI <30 mL/m2

3.56 (2.08-6.07)

<.001

3.35 (1.95-5.74)

<.001

CI <2.3 L/min/m2

2.16 (1.27-3.66)

.004

2.16 (1.28-3.65)

.004

SVI <30 mL/m2

2.09 (1.21-3.61)

.008

2.5 (1.43-4.36)

.001

CI <2.3 L/min/m2

1.85 (1.07-3.19)

.027

1.87 (1.08-3.23)

.025

SVI <30 mL/m2

2.13 (1.25-3.64)

.005

2.55 (1.49-4.39)

.001

CI <2.3 L/min/m2

1.24 (0.73-2.12)

.427

1.84 (1.04-3.25)

.036

SVI <30 mL/m2

4.36 (2.47-7.71)

<.001

4.21 (2.38-7.46)

<.001

CI <2.3 L/min/m2

2.02 (1.15-3.56)

.015

2.08 (1.18-3.68)

.002

.584 .073

.95

TTE within 3 days (n = 130) 2.72 (1.42-5.22)

.003 .88

TTE after 3 days (n = 128) 2.67 (1.48-4.83)

.001 .775

LVEF $50% (n = 122) 3.43 (1.81-6.48)

<.001

LVEF <50% (n = 136) SVI <30 mL/m2

1.42 (0.84-2.4)

.189

1.76 (1.03-2.98)

.038

CI <2.3 L/min/m2

1.27 (0.75-2.14)

.379

1.5 (0.88-2.55)

.136

BB, Beta-blocker; TTE, transthoracic echocardiography. Multivariate analysis was performed with the same parameters used in Table 2. Only SVI and CI groups are shown.

DISCUSSION LV output is a prognostic determinant in patients with HF, but whether a per-beat index, such as SVI, or a per-minute index, such as CI, is a better prognosticator has never been investigated. In this study, for the first time we provide evidence that SVI is a better predictor of outcome than CI in patients hospitalized with HF. This is based on the following observations. First, although in the univariate analysis (including the Kaplan-Meier analysis) both SVI and CI were significantly associated with outcome, in the multivariate evaluation, only SVI remained significantly associated (for both the primary and the combined end point of all-cause mortality and HF rehospitalization). Second, SVI was associated with outcome in both patients with and those without b-blocker therapy at presentation, whereas CI was not. Third, SVI was a prognostic determinant when assessed both within and after 3 days from admission, whereas CI was not. Finally, SVI further stratified prognosis of patients with normal or reduced CI, whereas CI did not determine a prognostic stratification in patients with reduced SVI. In our opinion, the better association of SVI with outcome is related mainly to its physiologic meaning. CI evaluates the ability of the heart to pump enough blood into the circulation to meet the body’s demands but depends also on factors unrelated to myocardial function, which act to modulate heart rate. SVI focuses more on LV contraction and is more directly related with the underlying cardiac disease and thus with prognosis. Further insights come from the analysis of the relationship between CI and SVI (Figure 5). This relationship is linear but has a wide scatter, and in some patients SVI and CI are divergent. Patients with normal SVI may have reduced CI (this may occur, e.g., if these patients are on b-blocker therapy). On the other hand, there are patients with

reduced SVI and normal CI (this can occur, in the absence of bblocker therapy, if a low SVI or hypoxygenation due to pulmonary congestion increases sympathetic activation and heart rate). In other words, for the same SVI, a wide spectrum of CI is possible depending on heart rate. However, when SVI is low, either with reduced or normal CI, prognosis is worse (Figure 3). These observations are reflected in the characteristics of the two subgroups of patients with low SVI and normal CI and with normal SVI and low CI (Supplemental Table 1). Whereas patients with low SVI and normal CI had higher heart rates at admission and during echocardiography, those with normal SVI and low CI were more often on b-blocker therapy at admission and had lower heart rates. In addition, patients with low SVI had lower systolic blood pressure at admission, lower LVEF values, and a higher prevalence of atrial fibrillation during echocardiography.

The Issue of Echocardiographic Timing The median time of the echocardiographic examination was 3 days from admission. This time reflects the manner in which echocardiographic examinations are performed at our hospital. For patients who need very early evaluations, the cardiology consultant performs a bedside scan using a pocket-sized handheld ultrasound device, and because these images are not stored in the central digital archive, they were not included in our study. In this study only the echocardiograms obtained by the hospital echocardiography laboratory were used. Generally, in patients with de novo acute HF or unknown cardiac function, echocardiography was performed earlier, whereas in patients with known cardiac function and in those responding to treatment, it was performed later. This is in agreement with current guidelines.16

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Mele et al 9

Figure 3 Kaplan-Meier survival according to subgroups of SVI and CI. Pairwise analysis results are in the text. Characterization of Overall Hemodynamic Status LV filling pressure was more frequently increased in patients with low LV forward flow status (63%-67% of patients), but was also often increased in patients with normal LV forward flow (55%-58% of patients; Table 2). These findings highlight that the hemodynamic profile of patients admitted with HF is heterogeneous. It has been suggested to combine LV forward flow assessment with LV filling pressure estimation to characterize the overall hemodynamic status of patients with HF.17,18 This is not possible using LVEF. In fact, as shown in our validation group, 44% to 45% of patients with normal LV forward flow status (SVI >30 mL/m2 or CI $2.3 L/min/m2) had reduced LVEFs (<50%; Table 2). Conversely, 30% to 35% of patients with reduced LV forward flow (SVI <30 mL/m2 or CI <2.3 L/min/m2) had normal LVEFs ($50%). This clearly shows that LVEF is not sufficient to adequately describe LV systolic function in patients with HF.

Impact of Different HF Phenotypes An important issue is the impact of LVEF and RV systolic function on the association of SVI and CI with outcome. In patients with LVEFs $50%, only SVI was associated with outcome in the multivariate Cox analysis. In patients with LVEFs <50%, SVI was associated with outcome in the univariate age-adjusted analysis and in the multivariate analysis performed without considering other echocardiographic indices of cardiac function, such as TAPSE. However, when TAPSE was included in the multivariate analysis, SVI was no longer

associated with outcome. No significant association was observed for CI in patients with reduced LVEF. These findings show that in patients with HF with reduced LVEF, SVI is a better prognosticator than CI, but RV systolic function predominates as an independent prognosticator over LV output. These results should be interpreted with caution because our study was not powered to compare SVI and CI in subgroups of patients with different LVEFs and RV function. Further investigations, therefore, are needed to verify the impact of different HF phenotypes on the association of SVI and CI with outcome. Results from Previous Studies Previous studies indicated that LV SVI provides prognostic information in patients with HF.19,20 De Marco et al.19 showed, in a large population-based sample, that low SVI was associated with a higher incident rate of congestive HF, independent of LVEF, LV geometry, and other major confounders. SVI was obtained normalizing SV by height in meters to the respective allometric power of 2.04, and a value #22/m2.04 was considered indicative of low SVI. Kamperidis et al.20 reported that low SV at discharge after surgical repair of severe secondary mitral regurgitation was an independent prognostic predictor of worse outcome and that each 10-mL increase in LV forward SV was independently associated with a 21% decrease in all-cause mortality and a 21% decrease in the combined end point. In those studies, however, SVI was not directly compared with CI, as we did in our investigation.

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Journal of the American Society of Echocardiography - 2019

Figure 4 Kaplan-Meier survival curves according to additional SVI and CI cut-off values. Comparisons between different SVI and CI subgroups are reported in the lower part of panels (A) and (B), respectively. Other investigators used stroke distance as a surrogate of SVI to predict outcomes in patients with HF.21,22 Tan et al.,21 in a subgroup of patients with HF, reduced LVEF, and low stroke distance (#10 cm), found that stroke distance was an independent predictor of death and LV assist device implantation, while LVEF and cardiac output did not show any correlation with outcome at the univariate analysis. Zhong et al.,22 in a study including 350 patients with HF, observed that a low stroke distance was an independent predictor of all-cause mortality regardless of whether LVEF was above or below 50%. In contrast, CI was not associated with mortality in the multivariate analysis. These latter studies, although based on the use of stroke distance, support our observation that a per-minute evaluation of LV output is a less powerful prognosticator than a per-beat evaluation. Selection of Different Cutoff Values In the present investigation, the cutoff value used for SVI was 30 mL/ m2. This cutoff value is lower than that generally used in clinical practice. In fact, SVI >35 mL/m2 is commonly considered normal, and a value #35 mL/m2 is routinely used to identify a low-flow aortic stenosis.5 The 35 mL/m2 cutoff value of SVI, however, has never been validated. Conversely, some observations from the literature indicate that this value is too high to separate a normal from abnormal LV systolic flow condition. For example, in a longitudinal population study of 2,524 individuals free of cardiovascular disease, 31% of subjects had SVI <35 mL/m2.23 In addition, Rusinaru et al.24 showed that

an SVI of 30 mL/m2 rather than 35 mL/m2 has prognostic value in aortic stenosis. The results of our study agree with these observations and support the use of a 30 mL/m2 SVI cutoff value to indicate a cardiac low-flow condition associated with adverse outcomes in patients with HF (Figure 4, Table 5). Reliability of the Doppler Echocardiographic Approach We measured LV output using the Doppler echocardiographic method and obtained reasonable observer variability in calculating SVI (5%-6%). This method was compared in several previous studies with invasive cardiac output25-28 and CI,1,29 also in the setting of low cardiac output2 and in the subset of patients with HF and reduced LVEF,3,4 and good agreement with invasive measures was generally reported.1-4,25-30 Currently, the Doppler echocardiographic measurement of LV SV is a routine evaluation and an integral component of the echocardiographic report in many echocardiography laboratories. It is commonly applied not only for assessment of LV systolic function but also to evaluate effective aortic valve area in aortic stenosis, mitral regurgitant volume and fraction, and Qp/Qs ratio in atrial septal defect.31 This approach has several advantages for the evaluation of LV output: it is practical, relatively fast, and applicable at patient bedside. A limitation is the inadequate visualization of the LVOT, which precludes a reliable measure of LVOT diameter. Although Doppler echocardiographic measures of LV output have been correlated with those obtained at

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Figure 5 Scatterplot of SVI versus CI. Cutoff values used for the primary objective of the validation study are indicated by the dotted lines.

Table 5 Cox regression analysis with relative risk for all-cause mortality for different SVI and CI subgroups Univariate HR (95% confidence interval)

SVI groups

P

Age-adjusted univariate HR (95% confidence interval)

.001

SVI >35 mL/m2 2

SVI <30 mL/m

CI $2.3 L/min/m2 CI 1.8-2.2 L/min/m2 2

CI <1.8 L/min/m

Referent

.991

1.07 (0.62-1.85)

.815

2.09 (1.37-3.19)

.001

2.58 (1.68-3.96)

<.001

.06 Referent

P

<.001

Referent

1.0 (0.58-1.74)

CI groups

Multivariate HR (95% confidence interval)

<.001

Referent

SVI 30-35 mL/m2

P

0.9 (0.47-1.74) 2.58 (1.6-4.15)

.009 Referent

.754 <.001 .694

Referent

1.46 (0.94-2.28)

.095

1.74 (1.11-2.73)

.016

.691

1.72 (1.04-2.84)

.034

1.92 (1.16-3.18)

.011

.591

Multivariate analysis was performed with the same parameters used in Table 2. Only SVI and CI groups are shown.

cardiac catheterization, it should be underlined that invasive hemodynamic measurements are still the gold standard of care. Study Limitations and Perspectives This was a retrospective investigation. However, because in our central echocardiography laboratory, examinations are always comprehensive and digitally stored, all necessary ultrasound data were available for analysis and were reevaluated for the study. Conversely, blood pressure was not consistently measured at the moment of the echocardiographic examination, so only blood pressure values at admission were used in this investigation. SVevaluation with pulsed-wave Doppler in the LVOT can be limited by causes of subaortic acceleration, such as relevant aortic regurgitation and hyper-

trophic obstructive cardiomyopathy. However, none of our patients had these conditions. Although we measured end-diastolic and end-systolic volumes to obtain the global SV and then calculate the LVEF, we did not use global SV to quantify blood ejected from the left ventricle. In fact, it is known that the two-dimensional evaluation of LV SV is limited by echocardiographic geometric modeling, which is inaccurate in the presence of aneurysms, asymmetric left ventricles, and wall motion abnormalities and by foreshortened apical views even in symmetrical left ventricles.32 The correlation observed in our study between global SV and Doppler LV forward flow (r = 0.536) is in line with the results of previous investigations showing only weak to moderate correlations.32,33 Echocardiographic measurements in this study reflect only one-time

12 Mele et al

evaluation in patients with decompensated HF. Future prospective studies may address the value of serial echocardiographic evaluations. Finally, because our patients were all admitted to the hospital for decompensated HF, the results of this study need confirmation in an ambulatory patient population with chronic stabilized HF.

CONCLUSION A per-beat evaluation of LV output obtained by SVI has a stronger association with outcome than a per-minute measure such as CI in patients hospitalized with HF. This observation has implication in selecting the appropriate index of LV output when assessing prognosis.

SUPPLEMENTARY DATA Supplementary data to this article can be found online at https://doi. org/10.1016/j.echo.2019.09.009.

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11. Magnin PA, Stewart JA, Myers S, VonRamm O, Kisslo JA. Combined Doppler and phased-array echocardiographic estimation of cardiac output. Circulation 1981;63:388-92. 12. Elkayam U, Gardin JM, Berkley R, Hugues CA, Henry WL. The use of Doppler flow velocity measurement to assess hemodynamic response to vasodilators in patients with heart failure. Circulation 1983;67:377-83. 13. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 14. Van Diepen S, Katz JN, Albert NM, Henry TD, Jacobs AK, Kapur NK, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136: e232-68. 15. Reynolds HR, Hochman JS. Cardiogenic shock current concepts and improving outcomes. Circulation 2008;117:686-97. 16. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975. 17. Abbas AE, Abdulla RK, Aggrawal A, Crile J, Lester SJ, Boura J. A novel echocardiographic hemodynamic classification of heart failure based on stroke volume index and left atrial pressure. Echocardiography 2017;34: 1417-25. 18. Mele D, Nardozza M, Ferrari R. Left ventricular ejection fraction and heart failure: an indissoluble marriage? Eur J Heart Fail 2018;20:427-30. 19. De Marco M, Gerdts E, Mancusi C, Roman MJ, Lønnebakken MT, Lee ET, et al. Influence of left ventricular stroke volume on incident heart failure in a population with preserved ejection fraction (from the Strong Heart Study). Am J Cardiol 2017;119:1047-52. 20. Kamperidis V, van Wijngaarden SE, van Rosendael PJ, Kong WK, Leung M, Sianos G, et al. Restrictive mitral valve annuloplasty: prognostic implications of left ventricular forward flow. Ann Thorac Surg 2017;104: 1464-70. 21. Tan C, Rubenson D, Srivastava A, Mohan R, Smith MR, Billick K, et al. Left ventricular outflow tract velocity time integral outperforms ejection fraction and Doppler-derived cardiac output for predicting outcomes in a select advanced heart failure cohort. Cardiovasc Ultrasound 2017; 15:18. 22. Zhong Y, Almodares Q, Yang J, Wang F, Fu M, Johansson MC. Reduced stroke distance of the left ventricular outflow tract is independently associated with long-term mortality, in patients hospitalized due to heart failure. Clin Physiol Funct Imaging 2018;38:499-502. 23. Chirinos JA, Rietzschel ER, De Buyzere ML, De Bacquer D, Gillebert TC, Gupta AK, et al. Arterial load and ventricular-arterial coupling: physiologic relations with body size and effect of obesity. Hypertension 2009;54: 558-66. 24. Rusinaru D, Bohbot Y, Ringle A, Mar
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29. Evangelista A, Garcia-Dorado D, Del Castillo HG, Gonzalez-Alujas T, Soler-Soler J. Cardiac index quantification by Doppler ultrasound in patients without left ventricular outflow tract abnormalities. J Am Coll Cardiol 1995;25:710-6. 30. Mele D, Andrade A, Bettencourt P, Moura B, Pestelli G, Ferrari R. From left ventricular ejection fraction to cardiac hemodynamics: role of echocardiography in evaluating patients with heart failure. Heart Fail Rev 2019. in press. 31. Qui~ nones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Stan-

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echaux S, Le Goffic C, Ennezat P-V, Semichon M, Castel A-L, Delelis F, et al. Quantitative assessment of primary mitral regurgitation using left ventricular volumes: a three-dimensional transthoracic echocardiographic pilot study. Eur Heart J Cardiovasc Imaging 2014;15:1133-9. 33. Nabeshima Y, Nagata Y, Negishi K, Seo Y, Ishizu T, Sato K, et al. Direct comparison of severity grading assessed by two-dimensional, threedimensional, and Doppler echocardiography for predicting prognosis in asymptomatic aortic stenosis. J Am Soc Echocardiogr 2018;31: 1080-90.

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SUPPLEMENTARY DATA

Supplemental Table 1 Baseline characteristics of the validation study population in four hemodynamic subgroups Low SVI, CI (n = 70 [27%])

Low SVI, normal CI (n = 19 [7%])

Normal SVI, low CI (n = 31 [12%])

76 (70-86)

Normal SVI, CI (n = 138 [54%])

P

Age, y

77 (67-85)

Sex, male

40 (57)

BMI, kg/m2

27 (23-29)

BSA, m2

1.9 (1.73-1.99)

History of HF

20 (29)

5 (26)

9 (29)

34 (25)

.919

History of AF

29 (41)

8 (42)

15 (48)

43 (31)

.208

Ischemic etiology

24 (34)

4 (21)

11 (36)

38 (28)

.535

Hypertension

44 (63)

14 (74)

20 (65)

107 (78)

.12

Diabetes

19 (27)

3 (16)

7 (23)

45 (33)

.358

CKD

20 (29)

9 (47)

12 (39)

42 (30)

.358

CAD

30 (43)

8 (42)

14 (45)

49 (36)

.634

COPD

10 (14)

2 (11)

3 (10)

28 (20)

.362

II

10 (14)

1 (5)

3 (10)

8 (6)

III

55 (79)

18 (95)

25 (80)

116 (84)

3 (10)

14 (10)

10 (53)

16 (52)

64 (46)

8 (42) 27 (24-32) 1.86 (1.64-1.94)

78 (68-85)

80 (71-85)

19 (61)

68 (49)

.398

27 (24-30)

26 (23-30)

.615

1.87 (1.69-2-02)

1.82 (1.65-1.96)

NYHA functional class

IV High NPs

.229

.322

5 (7)

0

36 (51)

SBP at admission, mm Hg

130 (110-150)

140 (110-155)

155 (128-175)

145 (130-160)

DBP at admission, mm Hg

80 (70-100)

80 (70-95)

80 (80-90)

80 (70-90)

Creatinine at admission, mg/dL

1.18 (0.96-1.7)

HR at admission, beats/min

100 (80-130)

Bradycardia (HR <60 beats/min) at admission

.559

1 (1)

1.38 (0.92-1.92)

1.21 (0.96-1.79)

100 (93-109)

78 (70-90)

0

.867 .003 .702

1.18 (0.93-1.74)

.949

90 (80-105)

.009

2 (7)

2 (1)

.265

Tachycardia (HR >100 beats/min) at admission

22 (31)

4 (21)

3 (10)

20 (15)

.014

Intravenous diuretics at admission

54 (77)

16 (84)

23 (74)

104 (75)

.843

TTE within 3 days

39 (56)

9 (47)

12 (39)

70 (51)

HR during TTE, beats/min

76 (67-86)

58 (53-65)

74 (66-81)

<.001

16 (52)

13 (9)

<.001

5 (4)

<.001

24 (17)

<.001

Bradycardia (HR <60 beats/min) during TTE

5 (7)

Tachycardia (HR >100 beats/min) during TTE

7 (10)

AF during TTE LVMI, g/m2

34 (49)

103 (89-108) 0 11 (58) 8 (42)

0 9 (29)

.464

111 (96-140)

99 (91-137)

116 (94-136)

113 (96-132)

.882

LVEDVI, mL/m2

68 (44-88)

57 (45-89)

60 (50-102)

64 (51-79)

.877

LVESVI, mL/m2

43 (21-65)

32 (19-62)

34 (22-75)

29 (21-46)

.092

LVEF, %

34 (27-55)

32 (30-59)

43 (30-56)

52 (43-59)

<.001

LVEF <50%

49 (70)

13 (68)

17 (55)

57 (41)

TAPSE, cm

1.4 (1.2-1.7)

1.6 (1.2-1.9)

1.8 (1.5-2)

1.9 (1.7-2.1)

33 (31-37)

SVI, mL/m2

23 (19-26)

27 (23-28)

CI, L/min/m2

1.8 (1.5-2)

2.5 (2.4-2.7)

Increased LV filling pressure

46 (85)

10 (71)

2 (1.8-2.2) 22 (82)

.001 <.001

41 (36-47)

<.001

2.9 (2.6-3.5)

<.001

76 (66)

.039 (Continued )

Mele et al 13.e2

Journal of the American Society of Echocardiography Volume - Number -

Supplemental Table 1 (Continued ) Low SVI, CI (n = 70 [27%])

Low SVI, normal CI (n = 19 [7%])

Normal SVI, low CI (n = 31 [12%])

Normal SVI, CI (n = 138 [54%])

P

Moderate MR

49 (70)

12 (63)

15 (48)

62 (45)

.005

Moderate AR

5 (7)

1 (5)

4 (13)

14 (10)

.718

Moderate TR

25 (36)

7 (37)

6 (19)

33 (24)

.153

b-blocker at admission

26 (37)

7 (37)

20 (65)

70 (51)

.045

ACE inhibitor/ARB at admission

26 (37)

10 (53)

16 (52)

81 (59)

.034

MRA at admission

20 (29)

2 (11)

6 (19)

19 (14)

.054

b-blocker at discharge

52 (77)

14 (74)

25 (81)

102 (77)

.947

ACE inhibitor/ARB at discharge

30 (43)

11 (58)

19 (61)

69 (50)

.323

MRA at discharge

34 (50)

9 (47)

17 (55)

62 (47)

Duration of hospitalization, days Death at follow-up

9 (6-14) 40 (57)

8 (5-17) 10 (53)

8 (5-13) 10 (32)

9 (5-15) 47 (34)

.86 .845 .007

HF at 6 months

14 (20)

5 (26)

4 (13)

21 (15)

.515

Composite end point

43 (61)

11 (58)

12 (39)

56 (41)

.02

ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; LVEDVI, LV end-diastolic volume index; LVESVI, LV end-systolic volume index; LVMI, LV mass index; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography. Continuous variables are expressed as median (interquartile range) and categorical variables as count (percentage).

13.e3 Mele et al

Journal of the American Society of Echocardiography - 2019

Supplemental Table 2 Cox regression analysis with relative risk for all-cause mortality and HF at 6 months Univariate HR (95% CI)

P

Age-adjusted univariate HR (95% CI)

P

Age (per 5 y)

1.21 (1.1-1.32)

Sex, male

1.37 (0.96-1.97)

.084

1.61 (1.12-2.31)

.011

BMI

1.01 (0.98-1.05)

.487

1.03 (0.99-1.07)

.148

HR at admission

1 (1-1.01)

.362

1 (1-1.01)

.283

HR during TTE

1 (0.99-1.01)

.983

1 (0.99-1.02)

.42

SBP at admission NYHA functional class

0.99 (0.99-1) 1 (0.65-1.54)

<.001

.023

0.99 (0.99-1)

.012

.998

0.96 (0.63-1.47)

.853

AF during TTE

1.63 (1.13-2.35)

.01

1.54 (1.07-2.23)

.022

High NPs

1.77 (1.23-2.54)

.002

1.73 (1.2-2.48)

.003

History of HF

1.76 (1.22-2.55)

.003

1.65 (1.14-2.38)

.009

Ischemic etiology

1.31 (0.9-1.9)

.156

1.31 (0.9-1.9)

.162

History of AF

1.39 (0.97-1.99)

.071

1.29 (0.9-1.85)

.17

Hypertension

1.46 (0.96-2.22)

.08

1.21 (0.79-1.86)

.383

Diabetes

1.18 (0.81-1.73)

.385

1.32 (0.89-1.94)

.164

CKD

2.21 (1.54-3.16)

<.001

CAD

1.31 (0.92-1.88)

.135

1.3 (0.91-1.86)

2.01 (1.4-2.88)

<.001

1.67 (1.09-2.54)

.018

1.59 (1.04-2.43)

.031

b-blocker at discharge

0.87 (0.57-1.32)

.506

0.9 (0.59-1.37)

.62

0.4 (0.28-0.58)

<.001

0.41 (0.28-0.6)

<.001

1.16 (0.8-1.66)

.438

1.25 (0.86-1.79)

.24

1 (0.29-3.4)

.996

0.55 (0.15-1.99)

.366

1.04 (0.73-1.49)

.822

1.21 (0.84-1.74)

.299

LVEDVI

1 (0.99-1.01)

.736

1 (1-1.01)

.384

LVMI

1 (0.99-1.01)

.884

1 (1-1.01)

.582

MRA at discharge LVEF LVEF <50%

P

1.23 (1.11-1.35)

<.001

1.6 (1.07-2.39)

.021

.265 .506 .224 1.65 (1.1-2.48)

.016

1.57 (1.04-2.37)

.032

.15

COPD ACE inhibitor/ARB at discharge

Multivariate HR (95% CI)

Moderate MR

1.15 (0.8-1.64)

.448

1.26 (0.88-1.8)

.207

Moderate AR

1.19 (0.66-2.16)

.567

1.04 (0.57-1.89)

.894

Moderate TR

1.29 (0.88-1.88)

.196

1.24 (0.85-1.82)

.267

Increased LV filling pressure

1.52 (0.95-2.44)

.08

1.58 (0.98-2.53)

.059

TAPSE (per 1-mm increase)

0.93 (0.88-0.97)

.001

0.92 (0.88-0.96)

<.001

SVI <30 mL/m2

1.87 (1.3-2.67)

.001

2.2 (1.53-3.17)

<.001

CI <2.3 L/min/m2

1.42 (1-2.03)

.053

1.59 (1.11-2.28)

.012

.06 0.55 (0.36-0.83)

.005

2.16 (1.46-3.19)

<.001

.135 .903

ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; LVEDVI, LV end-diastolic volume index; LVMI, LV mass index; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography.