Impact of milrinone on mitral annular velocity in ... - Springer Link

J Med Ultrasonics (2013) 40:111–118 DOI 10.1007/s10396-012-0405-4

ORIGINAL ARTICLE

Impact of milrinone on mitral annular velocity in patients with congestive heart failure Yasuyuki Hadano • Hiroshi Ogawa • Takatoshi Wakeyama • Akira Takaki • Takahiro Iwami • Masayasu Kimura • Mamoru Mochizuki • Yosuke Miyazaki Atsushi Hiratsuka • Masunori Matsuzaki

•

Received: 25 July 2012 / Accepted: 27 August 2012 / Published online: 10 October 2012 Ó The Japan Society of Ultrasonics in Medicine 2012

Abstract Purpose The purpose of this study is to assess the impact of milrinone on mitral annular velocity in patients with congestive heart failure. Method We studied 27 patients with congestive heart failure. All patients underwent transthoracic echocardiography both before and after administration of milrinone. We measured the early transmitral velocity (E) and the mitral annular early diastolic velocity (Ea). The ratio of E to Ea (E/Ea) was calculated. After the baseline echocardiography, milrinone was administered as a continuous infusion at a rate of 0.25 lg/kg/min. Echocardiographic measurements were repeated 4 h after milrinone was begun. Results After administration of milrinone, Ea was significantly increased, while E/Ea was significantly decreased. The population of 27 patients was divided into 20 (74 %) with left ventricular ejection fraction (LVEF) \50 % and seven (26 %) with LVEF C50 %. Ea was significantly increased in both groups, while E/Ea was significantly decreased. Conclusion Even low-dose milrinone produced an improvement in left ventricular (LV) diastolic function, as evidenced by an increase in Ea, and falls in LV filling pressures, as determined by a decrease in E/Ea, in patients

Y. Hadano (&) H. Ogawa T. Wakeyama A. Takaki T. Iwami M. Kimura M. Mochizuki Y. Miyazaki A. Hiratsuka Division of Cardiology, Tokuyama Central Hospital, 1-1 Kodacho, Shunan 745-8522, Japan e-mail: [email protected] M. Matsuzaki Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan

with congestive heart failure throughout a wide range of LV systolic function. Keywords Mitral annular velocity Milrinone Congestive heart failure

Introduction Milrinone, a selective phosphodiesterase III inhibitor, has been shown to lead to a significant improvement in the hemodynamic state of patients with severe congestive heart failure [1–4]. It has both inotropic and vasodilator properties, as well as a favorable effect on left ventricular (LV) diastolic function or lusitropic activity. This agent increases cardiac output and reduces systemic vascular resistance and LV filling pressures. Moreover, the drug exerts its hemodynamic effects without excessive changes in heart rate or increases in myocardial oxygen consumption [4]. Thus, milrinone may be a valuable alternative to conventional agents such as dobutamine and nitroprusside in the shortterm treatment of patients with congestive heart failure. The early diastolic velocity of the mitral annulus (Ea) obtained by tissue Doppler imaging (TDI) has been reported to be a preload-independent index for evaluating LV diastolic function in patients with heart disease and correlates inversely with the time constant (tau) of LV isovolumic relaxation [5–7]. When TDI is combined with pulsed-Doppler measurement of transmitral velocity in early diastole (E), the resultant E/Ea ratio correlates with invasively measured LV filling pressures [6, 8–11]. However, possible effects of milrinone on LV diastolic function evaluated by TDI-derived mitral annular velocity have not been assessed in patients with congestive heart failure. Therefore, the purpose of this study was to assess

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the impact of milrinone on mitral annular velocity for the noninvasive estimation of LV diastolic function using TDI in patients with congestive heart failure.

Methods Study population We studied 27 patients with severe congestive heart failure, i.e., New York Heart Association functional class III or IV, and with B-type natriuretic peptide level [300 pg/ml, to predict pulmonary capillary wedge pressure (PCWP) [15 mmHg [9]. All patients were in sinus rhythm and had a normal PQ interval on an electrocardiogram. Exclusion criteria were atrial fibrillation, paced rhythm, severe mitral regurgitation, mitral stenosis, mitral prosthesis, severe mitral annular calcification, acute myocardial infarction, unstable angina, severe hypotension (systolic blood pressure \80 mmHg), unstable arrhythmias, and cardiac surgery within the past 6 months. The institutional review board of Tokuyama Central Hospital approved the investigational protocol, and all patients gave written informed consent before participation. Echocardiography All patients underwent transthoracic echocardiography both before and after intravenous administration of milrinone. Studies were analyzed by an echocardiologist blinded to all clinical data. Patients were imaged in the left lateral position. An ultrasound instrument with a 2.5-MHz transducer (Aplio 80, Toshiba, Otawara, Japan) was used. Two-dimensional measurements were obtained according to the recommendations of the American Society of Echocardiography [12]. Left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume index (LVESVI) were obtained using the modified biplane Simpson’s method. LVEF \50 % was defined as reduced; LVEF C50 % was defined as preserved [13]. All Doppler profiles were recorded in an apical 4-chamber view as previously described [10, 11, 14]. The peak velocities of early (E) and late (A) mitral inflow, the deceleration time of the E wave (DcT), and the mitral A duration (MAd) were measured using pulsed-wave Doppler with the sample volume at the tip of the mitral valve leaflets. The peak systolic (LSa) and early (LEa) and late (LAa) diastolic velocities of the lateral mitral annulus were measured by pulsed-wave TDI. The peak systolic (SSa) and early (SEa) and late (SAa) diastolic velocities of the septal mitral annulus were also subsequently measured. Sa was computed from the average of LSa and SSa. Ea was computed from the average of LEa and SEa because this

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J Med Ultrasonics (2013) 40:111–118

approach has been shown to yield optimum accuracy in patients with regional wall motion abnormalities [8]. The ratios of E to A (E/A) and E to Ea (E/Ea) were calculated. The differences in mean blood pressure, LVEF, LVESVI, Sa, Ea, and E/Ea between the timings before and after administration of milrinone were calculated in patients with LVEF \50 % and those with LVEF C50 %. In each patient, the velocity waves of three consecutive cardiac cycles obtained during end-expiratory apnea were averaged. Study protocol After the baseline echocardiographic study, milrinone was administered as a continuous infusion at a rate of 0.25 lg/ kg/min without a loading dose. Echocardiographic measurements were repeated 4 h after the intravenous infusion of milrinone was begun [15]. All cardioactive medications were withheld during the study. Statistical analysis Data are presented as mean ± SD or median and interquartile range (IQR). Statistical analysis was performed using a statistical package (Stat-view, Berkeley, CA, USA). A paired t test was used to compare the results before and after administration of milrinone. The unpaired Student’s t test was used to compare differences between patients with LVEF \50 % and those with LVEF C50 %. A paired t test was also performed for the two groups to assess the influence of systolic function on the validity of these methods. Pearson’s correlation was used to investigate the correlations of delta Ea and delta E/Ea with delta mean blood pressure, delta LVEF, delta LVESVI, and delta Sa. A p value \0.05 was considered significant.

Results Clinical characteristics and concurrent medical programs of the study population are shown in Table 1. The age range was 42–97 years (mean 73 ± 13 years). Of the 27 patients, four (15 %) were categorized as New York Heart Association functional class III and 23 (85 %) as class IV. Five patients (19 %) had prior congestive heart failure. The etiology of heart failure was old myocardial infarction in 10 patients (37 %), dilated cardiomyopathy in nine patients (33 %), and hypertensive heart disease in eight patients (30 %). The median of A-type natriuretic peptide level was 285 pg/ml (IQR 140–469 pg/ml). The median of B-type natriuretic peptide level was 1,117 pg/ml (IQR 623–1,759 pg/ml). The range of estimated glomerular filtration rate


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Table 1 Patient characteristics All patients (n = 27)

LVEF \ 50 % [n = 20 (74 %)]

LVEF C 50 % [n = 7 (26 %)]

Age (years)

73 ± 13

72 ± 12

74 ± 16

Male/female

17/10

15/5*

2/5

New York Heart Association functional class

Table 2 Effects of milrinone on clinical and echocardiographic parameters in all patients Baseline

After milrinone

p value

Heart rate (beats/min)

89 ± 18

88 ± 16

0.54

Systolic blood pressure (mmHg)

147 ± 27

120 ± 24

\0.001

Diastolic blood pressure (mmHg)

86 ± 20

69 ± 17

\0.001

107 ± 20

86 ± 16

\0.001

III

4 (15 %)

4 (20 %)

0 (0 %)

IV

23 (85 %)

16 (80 %)

7 (100 %)

5 (19 %)

3 (15 %)

2 (29 %)

Mean blood pressure (mmHg)

Old myocardial infarction

10 (37 %)

9 (45 %)

1 (14 %)

LVEF (%)

33 ± 19

41 ± 19

\0.001

Dilated cardiomyopathy

9 (33 %)

9 (45 %)*

0 (0 %)

LVESVI (ml/m2) LV end-diastolic dimension (mm)

53 ± 28 60 ± 8

47 ± 27 59 ± 7

\0.001 \0.05

Hypertensive heart disease

8 (30 %)

2 (10 %)*

6 (86 %)

109 ± 29

95 ± 28

\0.001

A-type natriuretic peptide (pg/ml)

285 (140–469)

312 (140–531)

231 (120–289)

0.26

B-type natriuretic peptide (pg/ml)

1117 (623–1759)

Prior congestive heart failure Diagnosis

Transmitral flow E (cm/s)

Estimated glomerular filtration rate (ml/min/ 1.73 m2)

49.6 ± 21.4

Chronic kidney disease

18 (67 %)

1375 (774–1878)

54.8 ± 17.1*

12 (60 %)

698 (523–869)

34.6 ± 26.4

6 (86 %)

Baseline medications Diuretic

15 (56 %)

11 (55 %)

4 (57 %)

Nitroglycerin

6 (22 %)

4 (20 %)

2 (29 %)

Calcium channel blocker

6 (22 %)

2 (10 %)*

4 (57 %)

Beta-blocker

5 (19 %)

2 (10 %)

3 (43 %)

Carperitide

4 (15 %)

4 (20 %)

0 (0 %)

Angiotensin receptor blocker

4 (15 %)

2 (10 %)

2 (29 %)

A (cm/s)

84 ± 34

80 ± 36

E/A

1.46 ± 0.62

1.39 ± 0.69

0.37

DcT (ms)

141 ± 44

151 ± 41

0.29

MAd (ms)

119 ± 17

130 ± 15

\0.001

Lateral mitral annular velocity LSa (cm/s)

6.3 ± 2.7

7.7 ± 3.2

\0.001

LEa (cm/s)

6.9 ± 3.1

8.9 ± 3.1

\0.001

8.0 ± 3.9

9.3 ± 4.1

\0.05

LAa (cm/s) Septal mitral annular velocity SSa (cm/s)

6.3 ± 2.9

7.8 ± 3.6

\0.01

SEa (cm/s)

5.7 ± 2.1

7.3 ± 2.4

\0.001

SAa (cm/s) Sa (cm/s) Ea (cm/s) E/Ea

Digoxin

4 (15 %)

3 (15 %)

1 (14 %)

Dobutamine

3 (11 %)

3 (15 %)

0 (0 %)

Angiotensinconverting enzyme inhibitor

3 (11 %)

3 (15 %)

0 (0 %)

Dopamine

2 (7 %)

2 (10 %)

0 (0 %)

Data are mean ± SD or number (percentage). A- and B-type natriuretic peptide levels are presented as median (interquartile range) * p \ 0.05 for comparison between left ventricular ejection fraction (LVEF) \50 % and LVEF C50 %

was 11.3–92.0 ml/min/1.73 m2 (mean, 49.6 ± 21.4 ml/min/ 1.73 m2), and 18 patients (67 %) had chronic kidney disease. Clinical and echocardiographic parameters before and after administration of milrinone are summarized in Table 2. The range of baseline LVEF was 8–76 % (mean,

7.5 ± 3.2

8.1 ± 3.5

0.14

6.3 ± 2.7

7.7 ± 3.1

\0.001

6.3 ± 2.2

8.1 ± 2.6

\0.001

18.8 ± 6.7

12.4 ± 4.1

\0.001

Data are mean ± SD LVEF left ventricular ejection fraction, LVESVI left ventricular endsystolic volume index, LV left ventricle, E peak early diastolic velocity of transmitral flow, A peak late diastolic velocity of transmitral flow, E/A ratio of E to A, DcT deceleration time of the early diastolic wave of transmitral flow, MAd mitral A duration, LSa peak systolic velocity of the lateral mitral annulus, LEa peak early diastolic velocity of the lateral mitral annulus, LAa peak late diastolic velocity of the lateral mitral annulus, SSa peak systolic velocity of the septal mitral annulus, SEa peak early diastolic velocity of the septal mitral annulus, SAa peak late diastolic velocity of the septal mitral annulus, Sa average of LSa and SSa, Ea average of LEa and SEa, E/Ea ratio of E to Ea

33 ± 19 %). Heart rate showed no significant change after administration of milrinone. Both systolic and diastolic blood pressures were significantly decreased. LVEF was significantly increased, whereas LV end-diastolic dimension was significantly decreased. Of the conventional Doppler indices, transmitral E velocity was significantly decreased; however, A velocity, the E/A ratio, and DcT

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were unchanged. MAd was significantly increased. Of the TDI-derived indices, both LSa and SSa were significantly increased. Both LEa and SEa were also significantly increased. Ea was significantly increased (Fig. 1a), while the E/Ea ratio was significantly decreased (Fig. 2a). The population of 27 patients was divided into 20 (74 %) with LVEF \50 % and seven (26 %) with LVEF C50 %. The characteristics of the two groups are outlined and compared in Table 1. Clinical and echocardiographic parameters before and after milrinone in the two groups are summarized in Tables 3 and 4, respectively. Ea was significantly increased in both patients with LVEF \50 % and those with LVEF C50 % (Fig. 1b, c), while the E/Ea ratio was significantly decreased (Fig. 2b, c). The differences in mean blood pressure, LVEF, LVESVI, Sa, Ea, and E/Ea between the timings before and after administration of milrinone in the two groups are shown in Table 5. The correlations of delta Ea and delta E/ Ea with delta mean blood pressure, delta LVEF, delta LVESVI, and delta Sa are shown in Table 6. Delta E/Ea tended to correlate with delta mean blood pressure and delta LVESVI in patients with LVEF \50 %. There were no complications of milrinone infusions.


Discussion This study demonstrated that milrinone caused a significant increase in Ea and a significant decrease in E/Ea in patients with congestive heart failure; this was confirmed in both patients with reduced LVEF and those with preserved LVEF. To our knowledge, this is the first study to identify the impact of milrinone on mitral annular velocity for the noninvasive estimation of LV diastolic function using TDI in patients with congestive heart failure. Although a few studies reported the relationship between milrinone and TDI-derived indices, their subjects were limited to patients undergoing coronary artery bypass grafting [16, 17]. Milrinone is an agent used to treat patients with congestive heart failure. Thus, we focused on patients with congestive heart failure. The net effect of the positive inotropic, lusitropic, and vasodilator actions of milrinone is a significant hemodynamic improvement in patients with severe congestive heart failure [1–4]. This agent produces an increase in contractile force, as reflected by an increase in peak positive dP/dt. Milrinone markedly reduces systemic vascular resistance, mean arterial pressure, LV filling pressures, and right atrial pressure, without producing either significant

Fig. 1 Effects of milrinone on mitral annular early diastolic velocity (Ea) in all patients (a), those with left ventricular ejection fraction (LVEF) \50 % (b), and those with LVEF C50 % (c)

Fig. 2 Effects of milrinone on the ratio of early transmitral velocity to mitral annular early diastolic velocity (E/Ea) in all patients (a), those with left ventricular ejection fraction (LVEF) \50 % (b), and those with LVEF C50 % (c)

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Table 3 Effects of milrinone on clinical and echocardiographic parameters in patients with left ventricular ejection fraction (LVEF) \50 % Baseline

After milrinone

Table 4 Effects of milrinone on clinical and echocardiographic parameters in patients with left ventricular ejection fraction (LVEF) C50 %

p value

Baseline

After milrinone

p value


91 ± 19

88 ± 17

0.37


83 ± 17

85 ± 17

0.45


140 ± 24

119 ± 22

\0.001


164 ± 30

123 ± 30

\0.05


87 ± 21

72 ± 17

\0.001


84 ± 18

60 ± 13

\0.05

105 ± 20

88 ± 17

\0.001

Mean blood pressure (mmHg)

111 ± 21

81 ± 16

\0.05

Mean blood pressure (mmHg) LVEF (%)

24 ± 10

33 ± 11

\0.001

LVEF (%)

60 ± 10

67 ± 10

\0.001

LVESVI (ml/m2)

64 ± 24

57 ± 23

\0.001

LVESVI (ml/m2)

21 ± 13

17 ± 9

\0.05

LV end-diastolic dimension (mm)

62 ± 8

60 ± 7

\0.05

LV end-diastolic dimension (mm)

53 ± 6

53 ± 5

0.63

E (cm/s)

105 ± 24

91 ± 24

\0.001

E (cm/s)

121 ± 40

108 ± 35

\0.05

A (cm/s)

76 ± 31

68 ± 27

0.09

A (cm/s)

106 ± 37

111 ± 39

0.51

E/A

1.56 ± 0.68

1.52 ± 0.76

0.74

E/A

1.20 ± 0.37

1.02 ± 0.23

0.14

DcT (ms)

131 ± 38

138 ± 37

0.54

DcT (ms)

167 ± 51

185 ± 31

0.38

MAd (ms) 117 ± 17 Lateral mitral annular velocity

127 ± 15

\0.001

139 ± 9

0.07

Transmitral flow

Transmitral flow

MAd (ms) 125 ± 18 Lateral mitral annular velocity

LSa (cm/s)

5.4 ± 2.1

6.4 ± 2.1

\0.001

LSa (cm/s)

9.0 ± 2.6

11.4 ± 2.9

\0.05

LEa (cm/s)

6.7 ± 3.5

8.5 ± 3.4

\0.001

LEa (cm/s)

7.7 ± 1.7

10.1 ± 2.1

\0.01

LAa (cm/s)

7.1 ± 3.7

8.3 ± 3.6

0.12

LAa (cm/s)

10.4 ± 3.7

12.4 ± 4.2

0.13

SSa (cm/s)

5.3 ± 2.2

6.6 ± 2.4

\0.001

SSa (cm/s)

9.0 ± 2.8

11.1 ± 4.3

0.29

SEa (cm/s)

5.5 ± 2.1

6.8 ± 2.2

\0.001

SEa (cm/s)

6.4 ± 2.2

8.7 ± 2.4

\0.01

Septal mitral annular velocity

SAa (cm/s) Sa (cm/s) Ea (cm/s) E/Ea

Septal mitral annular velocity

6.7 ± 3.0

7.4 ± 3.1

0.11

5.3 ± 2.0

6.5 ± 2.1

\0.001

SAa (cm/s) Sa (cm/s)

6.1 ± 2.3

7.7 ± 2.6

\0.001

Ea (cm/s)

19.1 ± 6.5

12.5 ± 3.5

\0.001

E/Ea

9.9 ± 2.7

10.3 ± 3.7

0.72

9.0 ± 2.5

11.3 ± 2.9

0.1

7.1 ± 1.9

9.4 ± 2.1

\0.01

18.1 ± 7.5

12.1 ± 5.8

\0.01

Data are mean ± SD.

Data are mean ± SD.

LVEF left ventricular ejection fraction, LVESVI left ventricular endsystolic volume index, LV left ventricle, E peak early diastolic velocity of transmitral flow, A peak late diastolic velocity of transmitral flow, E/A ratio of E to A, DcT deceleration time of the early diastolic wave of transmitral flow, MAd mitral A duration, LSa peak systolic velocity of the lateral mitral annulus, LEa peak early diastolic velocity of the lateral mitral annulus, LAa peak late diastolic velocity of the lateral mitral annulus, SSa peak systolic velocity of the septal mitral annulus, SEa peak early diastolic velocity of the septal mitral annulus, SAa peak late diastolic velocity of the septal mitral annulus, Sa average of LSa and SSa, Ea average of LEa and SEa, E/Ea ratio of E to Ea


tachycardia or an increase in myocardial oxygen consumption [4]. Milrinone also causes an improvement in multiple indices of LV diastolic function, such as peak negative dP/dt and tau [3]. Mitral E-wave velocity was significantly decreased after milrinone in this study; however, this index is influenced by multiple interrelated factors, including LV relaxation

rate, atrial and ventricular compliance, and left atrial pressure [18]. To overcome these limitations in mitral inflow parameters, combinations of mitral flow velocity curves with other Doppler parameters have been proposed. Mitral annular motion obtained by TDI has been introduced to correct for the influences of preload and myocardial relaxation on transmitral flow. Previous studies

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Table 5 Differences in clinical and echocardiographic parameters between the timings before and after administration of milrinone in patients with left ventricular ejection fraction (LVEF) \50 % and those with LVEF C50 %

Delta mean blood pressure (mmHg) Delta LVEF (%) Delta LVESVI (ml/m2)

LVEF \ 50 % [n = 20 (74 %)]

LVEF C 50 % [n = 7 (26 %)]

-17 ± 9*

-30 ± 24

8.7 ± 6.5

6.6 ± 2.9

-7.2 ± 7.8

-4.8 ± 5.0

Delta Sa (cm/s)

1.2 ± 0.9

2.3 ± 3.1

Delta Ea (cm/s)

1.6 ± 1.6

2.4 ± 1.2

-6.5 ± 5.8

-5.9 ± 3.2

Delta E/Ea Data are mean ± SD.

LVEF left ventricular ejection fraction, LVESVI left ventricular endsystolic volume index, LV left ventricle, E peak early diastolic velocity of transmitral flow, A peak late diastolic velocity of transmitral flow, E/A ratio of E to A, DcT deceleration time of the early diastolic wave of transmitral flow, MAd mitral A duration, LSa peak systolic velocity of the lateral mitral annulus, LEa peak early diastolic velocity of the lateral mitral annulus, LAa peak late diastolic velocity of the lateral mitral annulus, SSa peak systolic velocity of the septal mitral annulus, SEa peak early diastolic velocity of the septal mitral annulus, SAa peak late diastolic velocity of the septal mitral annulus, Sa average of LSa and SSa, Ea average of LEa and SEa, E/Ea ratio of E to Ea * p \ 0.05 for comparison between left ventricular ejection fraction (LVEF) \50 % and LVEF C50 %

found that TDI-derived mitral E/Ea is the best single Doppler predictor of LV filling pressures [6, 8–11]. Dokainish et al. [9] demonstrated that optimal cutoffs for the prediction of PCWP [15 mmHg are E/Ea [15 in patients with impaired LVEF and [11 in patients with normal LVEF. Ea was significantly increased after milrinone in this study. This can be explained by the fact that milrinone improves tau [3] and that Ea correlates inversely with tau [5]. Furthermore, E/Ea was significantly decreased. This can be supported by the previous finding that milrinone reduces LV filling pressures [1–4] and that E/Ea has the best correlation with LV filling pressures and directionally follows changes in LV filling pressures [6, 8–11]. The current study confirms these previously reported basic hemodynamic effects of milrinone. It demonstrates that even low-dose milrinone produces an improvement in LV diastolic function, as evidenced by a rise in Ea, and falls in LV filling pressures, as determined by a reduction in E/Ea, in patients with congestive heart failure throughout a wide range of LV systolic functions. Despite the wide LVEF range, an improvement in Ea was considered to be produced by the direct effect of milrinone on LV relaxation. In patients with LVEF \50 %, the effect of milrinone on E/Ea may be associated with afterload reduction and

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Table 6 Correlation coefficients of differences in mitral annular early diastolic velocity (Ea) and the ratio of early transmitral velocity to mitral annular early diastolic velocity (E/Ea) with differences in clinical and echocardiographic parameters in patients with left ventricular ejection fraction (LVEF)\50 % and those with LVEF C50 % Delta Ea r

Delta E/Ea p

r

p

LVEF \50 % Delta mean blood pressure Delta LVEF Delta LVESVI Delta Sa LVEF C50 % Delta mean blood pressure Delta LVEF Delta LVESVI Delta Sa

-0.07

0.78

0.43

0.06

0.31

0.19

-0.05

0.85

0.11

0.65

-0.4

0.08

-0.08

0.75

-0.01

0.96

0.26

0.58

-0.18

0.7

0.58

0.18

0.4

0.38

-0.35

0.44

0.54

0.21

0.45

0.32

-0.13

0.79


increased LV systolic function (elastic recoil of LV) in addition to the direct effect of milrinone on LV relaxation, whereas in patients with LVEF C50 %, such additional findings with regard to E/Ea were not observed. The decrease in the mean E/Ea of 6.4, i.e., from 18.8 to 12.4, after low-dose milrinone in the present study indicates the decrease in PCWP of 5.8 mmHg predicted in the previous study [9]. Recently, Maeder et al. [19] suggested that there was no significant correlation between E/Ea and PCWP in heart failure with normal LVEF. In their study, PCWP was limited to relatively normal levels (B18 mmHg) and the mean E/Ea was 11.9 ± 3.3. The exclusion of patients with markedly increased PCWP may have impaired the correlation between E/Ea and PCWP. In our study, the mean E/ Ea in patients with preserved LVEF was 18.1 ± 7.5. The patients in our study appear to have more severe congestive heart failure than those in their study. The present study employed a fixed low dose of 0.25 lg/ kg/min. Larsson et al. [20] reported that the half-life of milrinone increased threefold in the presence of renal function impairment, compared with that in individuals whose renal function was normal. Mehra et al. [21]


reported that hypotension was a result of milrinone therapy in patients with renal insufficiency. Heart failure and chronic kidney disease are major and growing public health problems because aging of the population contributes to the increasing incidence of these diseases. More than 40 % of patients with heart failure have chronic kidney disease. The majority of patients in our study were aged patients with chronic kidney disease. Therefore, the dosage of milrinone was reduced appropriately to avoid the development of hypotension. Even low-dose milrinone may be effective in the present aging society. Limitations First, the number of patients in the present study was small; however, we were able to reach several significant observations. Second, to accurately elucidate the mechanisms in the relationship between Doppler indices and hemodynamics, simultaneous recordings of Doppler indices and LV filling pressures would be desirable. Third, although all cardioactive medications were withheld during the study, this may have biased the response to milrinone. That is, persistent reflex changes in response to baseline drugs or persistent conditioning effects of baseline drugs may have altered the hemodynamic responsiveness to milrinone. Finally, measurements of other diastolic parameters, such as pulmonary venous flow and flow propagation velocity, were not performed in this study, because previous investigators found that pulmonary venous flow indices and flow propagation velocity were weak predictors of LV filling pressures compared with E/Ea [6, 8–11]. Further studies are needed to determine the effects of milrinone on LV diastolic function in patients with congestive heart failure. Conclusion Even low-dose milrinone produces an improvement in LV diastolic function, as evidenced by an increase in Ea, and falls in LV filling pressures, as determined by a decrease in E/Ea, in patients with congestive heart failure throughout a wide range of LV systolic functions. Conflict of interest

None declared.

References 1. Maskin CS, Sinoway L, Chadwick B, et al. Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure. Circulation. 1983;67:1065–70.

117 2. Baim DS, McDowell AV, Cherniles J, et al. Evaluation of a new bipyridine inotropic agent—milrinone—in patients with severe congestive heart failure. N Engl J Med. 1983;309:748–56. 3. Monrad ES, McKay RG, Baim DS, et al. Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation. 1984;70:1030–7. 4. Monrad ES, Baim DS, Smith HS, et al. Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure. Circulation. 1986;73:III-168-74. 5. Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997;30: 474–80. 6. Nagueh SF, Middleton KJ, Kopelen HA, et al. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol. 1997;30:1527–33. 7. Tashiro H, Suda K, Tananari Y, et al. Impact of transcatheter closure of atrial septal defects on cardiac function. J Med Ultrason. 2012;39:147–53. 8. Rivas-Gotz C, Manolios M, Thohan V, et al. Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol. 2003;91:780–4. 9. Dokainish H, Zoghbi WA, Lakkis NM, et al. Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation. 2004;109:2432–9. 10. Hadano Y, Murata K, Liu J, et al. Can transthoracic Doppler echocardiography predict the discrepancy between left ventricular end-diastolic pressure and mean pulmonary capillary wedge pressure in patients with heart failure? Circ J. 2005;69:432–8. 11. Hadano Y, Murata K, Tanaka N, et al. Ratio of early transmitral velocity to lateral mitral annular early diastolic velocity has the best correlation with wedge pressure. Circ J. 2007;71:1274–8. 12. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr. 1989;2:358–67. 13. Yamamoto K. The spell of ventricular systolic function. J Med Ultrason. 2012;39:1–2. 14. Hadano Y, Murata K, Yamamoto T, et al. Usefulness of mitral annular velocity in predicting exercise tolerance in patients with impaired left ventricular systolic function. Am J Cardiol. 2006;97:1025–8. 15. Kobayashi S, Susa T, Tanaka T, et al. Low-dose b-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure. Circ J. 2012;76:1646–53. 16. Lobato EB, Willert JL, Looke TD, et al. Effects of milrinone versus epinephrine on left ventricular relaxation after cardiopulmonary bypass following myocardial revascularization: assessment by color M-mode and tissue Doppler. J Cardiothorac Vasc Anesth. 2005;19:334–9. 17. Couture P, Denault AY, Pellerin M, et al. Milrinone enhances systolic, but not diastolic function during coronary artery bypass grafting surgery. Can J Anesth. 2007;54:509–22. 18. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol. 1988;12:426–40. 19. Maeder MT, Karapanagiotidis S, Dewar EM, et al. Accuracy of Doppler echocardiography to estimate key hemodynamic variables in subjects with normal left ventricular ejection fraction. J Card Fail. 2011;17:405–12.

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118 20. Larsson R, Liedholm H, Andersson KE, et al. Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment. Eur J Clin Pharmacol. 1986;29:549–53.

123

J Med Ultrasonics (2013) 40:111–118 21. Mehra MR, Ventura HO, Kapoor C, et al. Safety and clinical utility of long-term intravenous milrinone in advanced heart failure. Am J Cardiol. 1997;80:61–4.