Heart and Vessels

, Volume 30, Issue 1, pp 89–97

Fasudil improves short-term echocardiographic parameters of diastolic function in patients with type 2 diabetes with preserved left ventricular ejection fraction: a pilot study

Authors

  • Rong Guo
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
  • Yang Su
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
  • Jing Yan
    • Department of Endocrinology, Shanghai Tenth People’s HospitalTongji University School of Medicine
  • Hui Sun
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
  • Jiakang Wu
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
  • Weijing Liu
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
    • Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of Medicine
Original Article

DOI: 10.1007/s00380-013-0458-3

Cite this article as:
Guo, R., Su, Y., Yan, J. et al. Heart Vessels (2015) 30: 89. doi:10.1007/s00380-013-0458-3
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Abstract

Left ventricular (LV) diastolic dysfunction is observed frequently in patients with type 2 diabetes; however, few studies have focused on the effect of the Rho-associated kinase inhibitor fasudil on cardiac performance in humans. We conducted a prospective pilot study to assess the impact of fasudil on LV diastolic function in patients with diabetes without systolic dysfunction. Two hundred and fifty eligible patients with type 2 diabetes (149 men [61.3 %] and 94 women [38.7 %]) with a mean age of 57.2 years were randomly assigned to fasudil (n = 122, 30 mg intravenously twice a day for 14 days) or placebo (n = 121) groups. Echocardiographic variables were measured at the baseline and 1 month after the intervention. Compared with the placebo group, the fasudil group showed a significant decrease in diastolic blood pressure and in the peak of late diastolic transmitral flow (Am) (P < 0.05 for both). Deceleration time (DT), isovolumic relaxation time (IVRT), the peak of early diastolic annular velocity (e′), the peak of late diastolic annular velocity, and E/e′ also exhibited a significant improvement (all, P < 0.05) after fasudil administration. Furthermore, the Em/Am ratio and IVRT, DT, and E/e′ values recorded after fasudil treatment in the subgroup with impaired LV relaxation significantly differed from the corresponding values in the subgroup with normal LV relaxation (all, P < 0.05). Fasudil improves short-term echocardiographic parameters of LV diastolic function in patients with type 2 diabetes with preserved left ventricular ejection fraction.

Keywords

Rho-kinase inhibitorFasudilDiastolic dysfunctionType 2 diabetes

Introduction

Cardiovascular disease (CVD) and its complications, including cardiac insufficiency, are the major causes of morbidity and mortality in patients with type 2 diabetes. The risk of CVD is increased by 2–4 times in patients with diabetes compared with individuals without diabetes [1]. The long-term vascular complications of diabetes and cardiomyopathy may have effects on myocardial function, cause a wide range of structural abnormalities, and eventually lead to diastolic and systolic dysfunction, or a combination of both [2, 3]. Left ventricular (LV) diastolic dysfunction is observed frequently in patients with type 1 or type 2 diabetes (even among asymptomatic ones) [4, 5]. In addition, it seems that diabetes is associated with a poor outcome in patients with diastolic heart failure [6]. Although evidence-based therapies have provided great benefits for the treatment of cardiovascular complications of diabetes, they have been used for improving cardiac diastolic function in diabetes in few cases.

Rho-associated kinases (ROCKs) that belong to the cAMP-dependent, cGMP-dependent, and protein kinase C (AGC) family of serine/threonine kinases are downstream effectors of Rho GTPases. ROCKs seem to contribute to numerous pathophysiological pathways that are triggered by hyperglycemia and represent promising molecular targets for cardioprotective treatment [7]. The Rho/ROCK pathway has also been involved in the regulation of vascular tone and proliferation, smooth muscle contraction, cell adhesion and motility, and reduction of vascular inflammation [79]. It has been reported that increased ROCK activities were associated with increased mortality and poor prognosis in several CVDs [10, 11]. Therefore, the Rho/ROCK pathway has been considered as a critical process in the pathogenesis of CVD. Recently, several animal experiments demonstrated that Rho/ROCK inhibition attenuated cardiomyopathy in diabetes and improved myocardial compliance [1214]. Therefore, a ROCK inhibitor would be a good candidate for treating diabetes and its complications [7, 15, 16].

The first-generation ROCK inhibitor fasudil has been studied widely and applied in clinical practice [17]. The safety and efficacy of fasudil in treating pulmonary arterial hypertension and cardiovascular and cerebrovascular diseases have been identified clearly in clinical trials [1820]. However, few studies have focused on the effect of Rho/ROCK inhibitors on cardiac performance in humans.

To investigate the benefits of fasudil, we conducted this prospective pilot study to assess the impact of the Rho/ROCK inhibitor fasudil on LV diastolic function in patients with diabetes without systolic dysfunction. Using echocardiography, we investigated whether fasudil improved short-term LV diastolic function in patients with type 2 diabetes with preserved left ventricular ejection fraction (LVEF).

Materials and methods

Participants

This study was a randomized, prospective, and controlled trial designed to evaluate the efficacy of a ROCK inhibitor in improving cardiac function in patients with type 2 diabetes. From January 2010 to April 2012, a total of 275 patients diagnosed with type 2 diabetes mellitus at our department or the endocrinology department were screened for this study. Physical examination and echocardiography were performed on admission, and diastolic dysfunction was defined as the presence of the relevant echocardiographic parameters described previously [21]. Patients were eligible to participate in the study if (1) their age ranged from 20 to 70 years; (2) they presented well-established type 2 diabetes with diastolic dysfunction; (3) LVEF was more than 50 % and in New York Heart Association (NYHA) class I or II; and (4) they had normal sinus rhythm. Exclusion criteria were as follows: any sign of type 1 diabetes, any acute diabetic complication, prior or recent myocardial infarction, atrial fibrillation or other significant arrhythmias, severe valvular heart diseases, uncontrolled hypertension (systolic blood pressure, >160 mmHg or diastolic blood pressure [DBP], >95 mmHg) or left ventricular hypertrophy, cardiomyopathy, severe hepatic or renal failure, chronic lung disease or any systemic disorder, anemia (hemoglobin level, <90 g/L), administration of additional drugs (e.g., antiarrhythmic or nonsteroidal drugs), major operations or trauma within 3 months, and pregnancy or child-bearing potential. Participants were allocated randomly using simple randomization procedures (computerized random numbers) to a placebo or fasudil group. Fasudil (30 mg; Chase Sun Pharmaceutical Co., Ltd, TJ, China) was administered intravenously over 30 min twice per day, starting within 24 h after randomization and continuation for 14 consecutive days. Normal saline solution was used as the placebo and was administered using the same protocol as that used for fasudil. No adjustment of study medication was permitted. This study was approved by the institutional ethics committee of Shanghai Tenth People’s Hospital, China, and informed consent was obtained from all patients enrolled.

Sample-size calculation

Published data [3, 22] suggest that 50 % of individuals with diabetes show diastolic dysfunction and that conventional drugs may reduce CV events by 11–15 %. We calculated that a targeted sample size of 200 patients was necessary to yield 90 % power to detect a significant difference between fasudil and placebo treatments at a 2-sided 5 % significance level. Considering the anticipated dropout rate of 20 %, we predicted the recruitment of no less than 250 patients into the current trial.

Doppler echocardiography and data collection

Investigations of LV function and other measurements were performed at baseline (on admission) and the first month after discharge. Echocardiographic examinations were performed at rest, with the patient semirecumbent in the left lateral position. All scans were performed by 2 experienced sonographers, by using a GE Vivid 7 (GE Healthcare, Piscataway, NJ, USA) ultrasound machine with a M4S (1.7–3.4 MHz) transducer, and reported by cardiologists with advanced training in echocardiography. LV measurements were recorded using the M-Mode from the parasternal long axis according to American Society of Echocardiography guidelines [23]. The ejection fraction was calculated using a modified Simpson’s rule from apical 4- and 2-chamber views [23].

The pulsed Doppler sampling volume was measured between the tips of the mitral valve leaflets to obtain maximum filling velocities in passive end-expiration by using a 3–5 mm sample volume. A standardized loop of 10 cardiac cycles was downloaded to the computer for analysis of the peak of early diastolic velocities (Em), the peak of late diastolic velocities (Am), the deceleration time of the peak E velocity (DT), and isovolumic relaxation time (IVRT). Pulsed wave Doppler tissue imaging (DTI) was acquired in the apical 4-chamber view placed over the myocardium, on the septum, at the level of the mitral annulus. Systolic motion (s′ wave) and early (e′) and late diastolic (a′) mitral annulus velocities were obtained. The e′ wave velocities from the septal and lateral walls were averaged and the ratio of the transmitral E wave to the average e′ velocity (E/e′ ratio) was calculated as an indicator of LV filling pressure. All measurements were made off-line on 3 separate beats and then averaged for all parameters. Echocardiographic, baseline demographic, clinical, and outcome data were collected for each patient.

Statistical analysis

Data were presented as the mean ± standard deviation (SD) or the percentage of incidence. Student’s t test or the Wilcoxon matched-pairs signed-ranks test was used to determine differences between groups for Gaussian-distributed or non-Gaussian-distributed data, respectively. Comparisons of proportions for dichotomous data were performed using the Chi squared test or Fisher’s exact test. A probability value <0.05 was considered significant. Statistical analyses were performed using the SPSS 15.0 software (SPSS Inc., Chicago, IL, USA), and a sample-size calculation was performed using the PASS 11.0 software package (NCSS LLC Inc., Kaysville, Utah, USA).

Results

Patient characteristics

Two hundred and seventy-five patients with type 2 diabetes were enrolled in this prospective study. Patients with atrial fibrillation rhythm (n = 2), a pacemaker (n = 3), primary valve disease (n = 3), prior myocardial infarction or coronary revascularization (n = 9), severe anemia (n = 1), end-stage diabetic nephropathy (n = 2), and poor echocardiographic window (n = 5) were ineligible for the study. Finally, a total of 250 patients were allocated randomly at a 1:1 ratio to receive fasudil or placebo treatment (Fig. 1). During the observational period, 7 participants (2.8 %) quit the study or were lost to follow-up (3 in the placebo group and 4 in the fasudil group). Thus, 243 patients with diabetes were included in the final analysis (121 in the placebo group and 122 in the fasudil group). Among these subjects, 149 were men (61.3 %) and 94 were women (38.7 %), with a mean age of 57.2 years. Intergroup differences in the age of patients, body mass index (BMI), history of disease, renal function, hemoglobin concentration, glycosylated hemoglobin A1c (HbA1c) level, blood pressure, heart rate, and recent condition of drug therapy were not significant (P > 0.05, Table 1).
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Fig. 1

Trial profile. Patients were allocated randomly to fasudil use

Table 1

Demographic and baseline clinical characteristics of the patients enrolled in the study

 

Fasudil group (n = 121)

Placebo group (n = 122)

P value

Age (years)

56.4 ± 8.5

58.0 ± 9.3

0.17

Gender (n, men/women)

79/42

70/52

 

Hypertension, n (%)

64 (52.9)

60 (49.2)

0.61

Hyperlipoidemia, n (%)

57 (47.1)

65 (53.3)

0.37

Tobacco use, n (%)

66 (54.5)

64 (52.5)

0.80

BMI (kg/m2)

27.5 ± 3.5

27.1 ± 3.3

0.88

CG-GFR (mL/min)

83.5 ± 15.3

82.0 ± 14.5

0.43

HbA1c (%)

6.6 ± 0.9

6.7 ± 0.9

0.30

Hemoglobin level (g/L)

134.2 ± 16.7

134.3 ± 15.6

0.96

Duration of diabetes (years)

4.6 ± 2.3

4.3 ± 2.1

0.29

SBP (mmHg)

127.0 ± 16.5

129.3 ± 14.7

0.25

DBP (mmHg)

74.6 ± 12.1

74.4 ± 11.3

0.92

Heart rate (beats/min)

75.1 ± 8.9

74.5 ± 8.8

0.68

Drug therapy

   

 Aspirin, n (%)

83 (68.6)

82 (67.2)

0.89

 Clopidogrel, n (%)

25 (20.7)

27 (22.1)

0.88

 Beta-blocker, n (%)

45 (37.2)

46 (37.7)

1.00

 ACEI/ARB, n (%)

49 (40.5)

51 (41.8)

0.90

 Statins, n (%)

71 (58.7)

77 (63.1)

0.51

 Diuretics, n (%)

21 (17.4)

18 (14.8)

0.60

 CCB, n (%)

56 (46.3)

59 (48.4)

0.79

 Insulin, n (%)

29 (24.0)

25 (20.5)

0.54

ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, BMI body mass index, CCB calcium-channel blockers, CG–GFR Cockcroft–Gault-glomerular filtration rate, DBP diastolic blood pressure, HbA1c glycosylated hemoglobin A1c, SBP systolic blood pressure

Echocardiographic findings

The differences between the baseline and first-month values of DBP, DT, IVRT, e′, a′, and E/e′ were not significant in the placebo group. Notably, in the fasudil group, there was a significant improvement in the decrease in DBP and Am, as well as in the values of LV relaxation (IVRT), LV stiffness (DT), and tissue Doppler (a′ and E/e′), after 1 month of treatment compared with the corresponding baseline values (all, P < 0.05; Table 2). The differences in DT, IVRT, a′, and E/e′ between the fasudil and placebo groups at the first month after intervention were also significant (all, P < 0.05; Table 2).
Table 2

Comparison of echocardiographic variables between the fasudil and placebo groups

 

Baseline

First month

LVDd (mm)

  

 Fasudil group

45.59 ± 4.78

45.28 ± 4.68

 Placebo group

45.16 ± 4.45

45.10 ± 4.43

LVPWd (mm)

  

 Fasudil group

9.71 ± 1.67

9.15 ± 1.54

 Placebo group

9.79 ± 1.74

9.56 ± 1.81

IVSd (mm)

  

 Fasudil group

9.15 ± 1.18

9.06 ± 1.11

 Placebo group

9.24 ± 1.23

9.11 ± 1.17

FS (%)

  

 Fasudil group

41.04 ± 5.33

40.85 ± 5.37

 Placebo group

41.17 ± 4.87

40.14 ± 4.56

LVEF (%)

  

 Fasudil group

63.68 ± 6.92

63.70 ± 5.88

 Placebo group

62.88 ± 7.10

63.07 ± 6.32

SBP (mmHg)

  

 Fasudil group

126.9 ± 16.5

128.8 ± 17.3

 Placebo group

129.3 ± 14.7

129.4 ± 12.5

DBP (mmHg)

  

 Fasudil group

77.8 ± 14.0

76.4 ± 8.9a

 Placebo group

74.4 ± 11.3

72.7 ± 10.7

Heart rate (beats/min)

  

 Fasudil group

75.1 ± 8.9

74.9 ± 8.6

 Placebo group

74.5 ± 8.8

74.6 ± 10.7

Em (cm/s)

  

 Fasudil group

78.83 ± 19.19

78.88 ± 17.53

 Placebo group

79.88 ± 18.69

78.42 ± 16.11

Am (cm/s)

  

 Fasudil group

80.09 ± 10.42

77.47 ± 10.01a

 Placebo group

80.14 ± 10.94

79.07 ± 10.58

Em/Am ratio

  

 Fasudil group

1.01 ± 0.36

1.05 ± 0.35

 Placebo group

1.02 ± 0.33

1.01 ± 0.29

DT (ms)

  

 Fasudil group

256.20 ± 60.86

251.80 ± 54.7a,b

 Placebo group

251.65 ± 54.90

248.77 ± 54.25

IVRT (ms)

  

 Fasudil group

112.85 ± 22.91

104.96 ± 19.58a,b

 Placebo group

109.10 ± 24.27

109.71 ± 25.26

e′ (cm/s)

  

 Fasudil group

10.53 ± 2.73

10.63 ± 2.95

 Placebo group

10.99 ± 2.47

10.40 ± 2.23

a′ (cm/s)

  

 Fasudil group

15.40 ± 2.81

14.64 ± 3.46a,b

 Placebo group

15.03 ± 2.34

14.79 ± 3.50

E/e′

  

 Fasudil group

8.70 ± 2.27

7.87 ± 2.12b,c

 Placebo group

8.52 ± 2.10

8.74 ± 2.18

a′ peak of late diastolic annular velocity, Am peak of late diastolic transmitral flow, DT deceleration time, e′ peak of early diastolic annular velocity, Em peak of early diastolic transmitral flow, FS fractional shortening, LVDd left ventricular diastolic diameter, LVEF left ventricular ejection fraction, LVPWd left ventricular posterior wall diastolic thickening, IVRT isovolumic relaxation time, IVSd interventricular septum diastolic thickening

aP < 0.01 versus the baseline

bP < 0.05 versus the placebo group

cP < 0.05 versus the baseline

There were no significant differences between the baseline and first-month values of left ventricular diastolic diameter (LVDd), left ventricular posterior wall diastolic thickening (LVPWd), interventricular septum diastolic thickening (IVSd), fractional shortening (FS), LVEF, heart rate, systolic blood pressure (SBP), Em, and Em/Am ratio both in the placebo and fasudil groups (Table 2).

Subgroup analysis of diastolic dysfunction

Cardiac diastolic dysfunction included impaired LV relaxation, pseudonormal LV filling (PNF), and restrictive mitral inflow pattern, as reported previously [21]. The placebo group consisted of 82 cases with impaired LV relaxation (E/A, 0.85 ± 0.07; IVRT, 122.93 ± 11.53 ms; and DT, 280.49 ± 38.09 ms), 35 cases with PNF (E/A, 1.42 ± 0.36; IVRT, 80.00 ± 14.78 ms; and DT, 189.71 ± 29.23 ms), and 5 cases with a restrictive mitral inflow pattern (E/A, 2.15 ± 0.04; IVRT, 50.00 ± 6.73 ms; and DT 116.00 ± 29.39 ms). In the fasudil group, 84 individuals presented with impaired LV relaxation (E/A, 0.85 ± 0.09; IVRT, 119.17 ± 11.04 ms; and DT, 286.24 ± 41.69 ms), 30 with PNF (E/A, 1.21 ± 0.15; IVRT, 97.33 ± 9.29 ms; and DT, 193.00 ± 44.88 ms), and 7 with a restrictive mitral inflow pattern (E/A, 2.22 ± 0.15; IVRT, 53.57 ± 6.93 ms; and DT, 120.00 ± 13.09 ms). After 2 weeks of fasudil treatment, 73 patients had impaired LV relaxation, 23 had PNF, and 5 had a restrictive mitral inflow pattern (Fig. 2). There was a significant decrease in the number of patients with impaired LV relaxation after fasudil treatment (P < 0.001). Moreover, Em/Am ratios (0.85 ± 0.09 vs. 0.91 ± 0.19), DT (286.24 ± 41.69 vs. 272.59 ± 55.66 ms), IVRT (124.05 ± 12.62 vs. 118.45 ± 15.01 ms), and E/e′ (8.6 ± 1.5 vs. 7.7 ± 1.5) changed in the impaired LV relaxation subgroup after 1 month of treatment. There were significant differences in the diastolic parameters of mitral inflow (Em/Am ratio, DT, and IVRT) and those of tissue Doppler (E/e′) between the baseline and first-month follow-up (all, P < 0.05; Fig. 3); similar differences were also observed between the fasudil and placebo groups at the first month (all, P < 0.05; Fig. 4). With the exception of the differences in E/e′ in the PNF subgroup and DT in the restrictive filling pattern subgroup (all, P < 0.05; Fig. 3), there were no significant changes in the PNF subgroup and restrictive filling pattern subgroup compared with the subgroup with a normal filling pattern (P > 0.05; Fig. 3).
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Fig. 2

Change in the number of patients in the 3 subgroups after fasudil treatment. The placebo group consisted of 82 cases with impaired LV relaxation, 35 cases with PNF, and 5 cases with a restrictive mitral inflow pattern. In the fasudil group, 84 individuals presented with impaired LV relaxation, 30 with PNF, and 7 with a restrictive mitral inflow pattern. After 2 weeks of fasudil treatment, 73 patients had impaired LV relaxation, 23 had PNF, and 5 had a restrictive mitral inflow pattern

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Fig. 3

Comparisons of 1-month cardiac diastolic parameters after fasudil treatment with the corresponding baseline levels in 3 diastolic dysfunction subgroups. a In the subgroup with impaired LV relaxation, the Em/Am ratio significantly increased, and DT, IVRT and E/e′ significantly decreased in the first month compared to the corresponding baseline values. b Only E/e′ significantly decreased after 1 month of treatment in the PNF subgroup compared to the baseline value. c In the subgroup with a restrictive mitral inflow pattern, there were no marked changes after 1 month of treatment compared to baseline, with the exception of the differences in the DT value

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Fig. 4

Comparisons of cardiac diastolic parameters in the subgroup with impaired LV relaxation after fasudil treatment with those observed in the placebo group at the first month of discharge. a After 1 month of discharge, the Em/Am ratio significantly increased compared to that in the placebo group. b After treatment, DT decreased in the subgroup with impaired LV relaxation. c IVRT significantly decreased compared to that in the placebo group. d After 1 month of discharge, E/e′ also significantly decreased compared to that in the placebo group

Clinical outcomes

No drug-related serious adverse events were observed in any of the patients over the course of the observation. All-cause death, abnormal liver function, bleeding, fever, hypotension, drug eruption, arrhythmia, and edema were not observed during the treatment and follow-up periods.

Discussion

This was a randomized controlled clinical trial that was designed to assess the effect of fasudil on cardiac diastolic function in patients with type 2 diabetes. Our findings revealed that fasudil injection significantly improved first-month diastolic parameters compared with the placebo treatment. Therefore, the results of the present study suggest that additional administration of a Rho/ROCK inhibitor might be effective and safe in improving cardiac diastolic function in patients with diabetes, beyond the known effects of the contemporary therapeutic strategies.

The prevalence of cardiac diastolic dysfunction or diastolic heart failure is increasing gradually; however, the rate of death from this disorder has remained unchanged over the past years [24]. Patients with diabetes had a high risk of CVDs and diabetic complications that increased the risk of heart failure in the Framingham study [3, 4]. Füchtenbusch et al. [25] found that hyperglycemia and insulin resistance were directly involved in the progression of diastolic dysfunction to chronic diastolic heart failure. Traditional treatment of diastolic dysfunction or diastolic heart failure in patients with diabetes is the same as that in patients without diabetes and includes the use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB), beta-blockers, diuretics, and aldosterone inhibitors. Although ACEI/ARB and beta-blockers have been shown to prevent cardiac mortality in patients with systolic heart failure, these agents did not yield similar results in patients with diastolic dysfunction or diastolic heart failure. Moreover, several randomized clinical trials (RCTs) published previously did not find contemporary pharmacotherapy to markedly reduce the risk of cardiac death [2628]. In addition, it is important for clinicians to identify diastolic abnormalities early, because early detection and intervention might provide a useful method to prevent worsening of diabetes-associated cardiac dysfunction.

Diastolic function is determined mainly by myocardial relaxation, passive mechanical properties, and myocardial stiffness. Several lines of evidence have demonstrated that Rho/ROCK inhibitors not only increased the expression of endothelial NO synthase (eNOS) in vivo or in vitro but also had an influence on the activity of myosin phosphatase by inducing the phosphorylation of its myosin-binding subunit [29, 30]. The favorable effects of these agents might have an impact on LV relaxation and LV filling pressures. Moreover, recent studies have shown that inhibition of ROCK attenuates the progression of diabetic-related disorders via multiple mechanisms, including inhibition of myocardial fibrosis, improvement of oxidative stress, and inhibition of myocardial apoptosis [12]. Fukui [31] found that long-term inhibition of Rho-kinase using fasudil significantly decreased the collagen phenotype shift and production of superoxide in an animal model of diastolic heart failure. It is also plausible that fasudil attenuates the hyperglycemia-induced monocyte–endothelial cell adhesion, which has been reported to have therapeutic potential in preventing diabetes-associated vascular inflammation and atherogenesis [32]. Myocardial stiffness can be improved by decreasing myocardial fibrosis and attenuating oxidative stress. Therefore, although the mechanism underlying the improved diastolic function observed in the present research remains uncertain, we presume that attenuation of myocardial stiffness might play an important role in the improvement of cardiac function associated with fasudil treatment.

Our study demonstrated significant decreases in DBP, Am, DT, IVRT, e′, a′, and E/e′ in the fasudil group compared with the corresponding values in the placebo group. In addition, significant changes in parameters of tissue Doppler imaging were also recorded in the fasudil group. Moreover, we found that Em/Am ratio, IVRT, DT, e′, a′, and E/e′ values were significantly different in the impaired LV relaxation subgroup of the fasudil group compared with the corresponding baseline values and values in the placebo groups (P < 0.05). Our findings might also have implications regarding the safety of fasudil administration to patients with diabetes with preserved LVEF as no severe adverse effects were observed during the therapy and follow-up periods.

Thus, the clinical application of fasudil for the treatment and prevention of diabetes-associated LV diastolic dysfunction was effective and safe. Previous studies demonstrated that pioglitazone was safe and effective in patients with type 2 diabetes mellitus [33] and might have potential benefits regarding LV diastolic function in type 2 diabetes [34]. Our results further suggest that the Rho/ROCK inhibitor fasudil is likely to have a cardioprotective effect by improving diastolic function, because the diastolic values observed in the fasudil group were significantly changed compared with those observed at the baseline, without apparent adverse effects. Moreover, the current study demonstrated the presence of an additional beneficial effect of fasudil on cardiac function in patients with diabetes.

The relatively small sample size used here was the major limitation of our study. In addition, the majority of the participants were men and many were receiving antihypertensive treatment and statin therapy, which might have influenced the echocardiographic measurements. Although the patients enrolled had no medical history of coronary artery diseases, microvascular lesions and small-vessel lesions might be present in these patients with diabetes, which may contribute to the variability observed among the participants. The echocardiographic variables measured in this study were not sufficient to confirm the improvement of diastolic dysfunction, and the lack of specific information about the subgroups of patients with different degrees of diastolic impairment hampered the evaluation of the effects of fasudil treatment. Finally, larger-scale, multicenter, randomized, and long-term trials are needed to confirm the effects of fasudil on diabetes-associated diastolic dysfunction.

In summary, treatment with the Rho/ROCK inhibitor fasudil for 2 weeks improved short-term echocardiographic parameters of diastolic function in patients with type 2 diabetes without LV systolic impairment.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81070107).

Conflict of interest

The authors declare that they have no conflicts of interest.

Copyright information

© Springer Japan 2014