Publications by authors named "Akihiro Hirashiki"

66 Publications

Short physical performance battery score and driving a car are independent factors associated with life-space activities in older adults with cardiovascular disease.

Geriatr Gerontol Int 2021 Oct 6;21(10):900-906. Epub 2021 Aug 6.

Department of Rehabilitation, National Center for Geriatrics and Gerontology, Obu, Japan.

Aim: Decreased use of life spaces, as reflected in decreased Life-Space Assessment (LSA) scores, is associated with poor prognosis in older adults. The purpose of this study was to examine factors affecting the extent of life-space activities in older adults with cardiovascular disease.

Methods: We carried out a prospective observational study in 98 older adults (minimum age 65 years; mean age 79.5 ± 7.4 years) who were admitted to our hospital due to cardiovascular disease. Once their medical condition was stable, they underwent cardiopulmonary exercise testing, echocardiography and physical evaluation, and completed questionnaires.

Results: The LSA score was significantly associated with the ability to drive a car (driving 95.1 ± 21.1 points, not driving 60.4 ± 30.3 points, P < 0.001). In addition, LSA was significantly correlated with age; peak VO ; brain natriuretic peptide; and Short Physical Performance Battery, Geriatric Depression Scale and Mini-Mental State Examination scores. In a multiple regression analysis, Short Physical Performance Battery and driving a car were significantly associated with LSA (β = 0.28, β = 0.37, respectively).

Conclusion: Assessment of motor function and social factors in addition to clinical cardiac function might be important to understand the complete context of life-space activity in older adults with cardiovascular disease. Geriatr Gerontol Int 2021; 21: 900-906.
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http://dx.doi.org/10.1111/ggi.14254DOI Listing
October 2021

Peak Work Rate during Exercise Could Detect Frailty Status in Elderly Patients with Stable Heart Failure.

Int Heart J 2019 Nov 15;60(6):1366-1372. Epub 2019 Nov 15.

Department of Cardiology, Nagoya University Graduate School of Medicine.

The Kihon Checklist (KCL) is a reliable tool for determining frailty status in the elderly. However, there is no information in the literature about the relationship between frailty status and exercise capacity. Here, we examined the associations between cardiopulmonary exercise testing parameters and frailty status in elderly patients with stable heart failure (HF).Ninety-two elderly patients with stable HF were evaluated using cardiopulmonary exercise testing and the KCL. A KCL score of 0-3 was classified as robust, 4-7 as pre-frail, and ≥ 8 as frail.Mean age, peak VO, and KCL score were 81.7 years, 13.2 mL/kg/minute, and 10.7, respectively. KCL score was significantly correlated with peak VO (r = -0.527, P < 0.001) and peak work rate (r = -0.632, P < 0.001). In patients with frailty (n = 63), the peak work rate (WR) was significantly lower than it was in patients without frailty (n = 29; 39.9 versus 69.5 W, respectively; P < 0.001). Multivariate analysis revealed that peak WR and peak systolic blood pressure were significant, independent predictors of frailty (β = -0.108 and -0.045, respectively). In a diagnostic performance plot analysis, a cutoff value for peak WR of 51.9 W was the best predictor of frailty.Frailty status was significantly associated with peak WR and peak systolic blood pressure in elderly patients with stable HF. Therefore, cardiopulmonary exercise testing may be useful for assessing frailty status in this patient population.
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http://dx.doi.org/10.1536/ihj.19-120DOI Listing
November 2019

Medium-term health-related quality of life in patients with pulmonary arterial hypertension treated with goal-oriented sequential combination therapy based on exercise capacity.

Health Qual Life Outcomes 2019 Jun 14;17(1):103. Epub 2019 Jun 14.

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan.

Background: Pulmonary arterial hypertension (PAH) remains a life-threatening condition, despite modern therapies. We prospectively investigated the therapeutic health-related quality of life (HRQOL) effects of goal-oriented sequential combination therapy based on exercise capacity in patients newly diagnosed with PAH.

Methods: To examine the changes in HRQOL in PAH patients, we treated 30 patients newly diagnosed with PAH with goal-oriented sequential combination therapy based on exercise capacity. We monitored exercise capacity by cardiopulmonary exercise testing and observed the benefit of using a peak VO cut-off of 15 mL/kg/min to guide combination therapy. First-line treatment was an endothelin receptor antagonist (ERA); second-line treatment was the addition of a phosphodiesterase-5 inhibitor (PDE-5I). At baseline and at 3, 6, and 12 months, HRQOL was evaluated by using the eight-item Medical Outcomes Survey Short Form Health Survey.

Results: At 12 months, 100% of PAH patients were receiving an ERA, and 82% an ERA + PDE-5I. The mean physical component summary (PCS) score was 33.5 at baseline, 41.2 at 3 months, 40.8 at 6 months, and 42.0 at 12 months, and the mean mental component summary (MCS) scores were 45.6, 47.0, 50.0, and 50.1, respectively. PCS score was significantly greater at 3 months than at baseline (P = 0.035). MCS score was comparable at 3 months and at baseline, but was significantly greater at 6 and 12 months than at baseline (P = 0.033, P = 0.028, respectively). Thus, PCS score improved soon after initiation of therapy, and MCS score improved later.

Conclusions: Together, these results suggest that goal-oriented sequential combination therapy based on exercise capacity improves HRQOL in patients with PAH.
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http://dx.doi.org/10.1186/s12955-019-1178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570916PMC
June 2019

Goal-Oriented Sequential Combination Therapy Evaluated Using Cardiopulmonary Exercise Parameters for the Treatment of Newly Diagnosed Pulmonary Arterial Hypertension - Goal-Oriented Therapy Evaluated by Cardiopulmonary Exercise Testing for Pulmonary Arterial Hypertension (GOOD EYE).

Circ Rep 2019 Jun 2;1(7):303-311. Epub 2019 Jun 2.

Department of Cardiology, Nagoya University Graduate School of Medicine Nagoya Japan.

Many treatment options are available for pulmonary arterial hypertension (PAH), but specific recommendations for long-term treatment are unavailable. We compared prognosis in PAH patients receiving goal-oriented, sequential combination therapy evaluated using cardiopulmonary exercise testing (CPX) parameters or conventional empiric therapy. The Goal-Oriented Therapy Evaluated by Cardiopulmonary Exercise Testing for Pulmonary Arterial Hypertension (GOOD EYE) study was a multicenter, retrospective/prospective study in which a total of 129 patients with newly diagnosed PAH were enrolled (goal-oriented sequential combination therapy, n=42; conventional empiric therapy, n=87). Patients in the goal-oriented therapy group received sequential combination therapy, the efficacy of which was regularly evaluated using CPX parameters. Patients in the conventional empiric therapy group received conventional empiric therapy. The primary endpoint was cardiovascular death. In the goal-oriented therapy group, plasma brain natriuretic peptide, mean pulmonary arterial pressure, pulmonary vascular resistance, and 6-min walk test were significantly improved at 12 months compared with baseline. Survival in the goal-oriented therapy group at 1, 2, and 3 years (97.6%, 95.2%, and 86.0%, respectively) tended to be higher than that in the conventional empiric therapy group (P=0.082). Goal-oriented sequential combination therapy evaluated using CPX parameters may be associated with a favorable prognosis compared with conventional empiric therapy in patients with newly diagnosed PAH.
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http://dx.doi.org/10.1253/circrep.CR-19-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892494PMC
June 2019

Left Ventricular Relaxation Half-Time as a Predictor of Cardiac Events in Idiopathic Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy With Left Ventricular Systolic and/or Diastolic Dysfunction.

Am J Cardiol 2019 08 9;124(3):435-441. Epub 2019 May 9.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: Diastolic dysfunction preceding systolic dysfunction is considered an important interaction in cardiomyopathy with poor prognosis. The aim of this study was to compare left ventricular (LV) isovolumic relaxation with the other parameters as a potential prognostic marker for patients with idiopathic dilated cardiomyopathy (IDC) and hypertrophic cardiomyopathy (HC).

Methods: A total of 145 patients with IDC and 116 with HC were evaluated for hemodynamic parameters; LV pressure was directly measured by a micromanometer catheter, and relaxation half-time (T) was used to determine LV isovolumic relaxation. The median follow-up period was 4.7 years.

Results: The mean ages of the patients with IDC and HC were 52.0 ± 12.0 and 57.1 ± 12.4 years, respectively. Each patient group was further divided into 2 groups based on the median value of T: (1) <41.0 ms (D-L group) and ≥41.0 ms (D-H group) (2) <38.5 ms (H-L group) and ≥38.5 ms (H-H group). Kaplan-Meier analysis showed a significantly higher probability of cardiac events in the D-H group than in the D-L group (p = 0.001) and in the H-H group than in the H-L group (p = 0.028). Further, Cox proportional hazard regression analysis revealed that T was an independent predictor of cardiac events for patients with IDC (hazard ratio 1.109; p = 0.007) and HC (hazard ratio 1.062; p = 0.041). In conclusion, regardless of the type of cardiomyopathy, T as a measure of LV isovolumic relaxation function was found to be associated with the occurrence of cardiac events.
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http://dx.doi.org/10.1016/j.amjcard.2019.05.005DOI Listing
August 2019

Usefulness of scoring right ventricular function for assessment of prognostic factors in patients with chronic thromboembolic pulmonary hypertension.

Heart Vessels 2018 Oct 27;33(10):1220-1228. Epub 2018 Apr 27.

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya, 466-8560, Japan.

Right ventricular (RV) function is associated with prognosis in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to establish an RV dysfunction score using RV echocardiographic parameters to clarify the clinical characteristics in patients with CTEPH and to compare RV dysfunction score with parameters such as World Health Organization (WHO) functional class, hemodynamics, exercise capacity, and plasma BNP level. We enrolled 35 inpatients with CTEPH (mean age, 62 ± 15 years, 15 males). We constructed 'an RV dysfunction score' calculated as the summation of each point awarded for the presence of four parameters: tricuspid annular plane systolic excursion (TAPSE) < 16 mm, 1 point; tissue Doppler-derived tricuspid lateral annular systolic velocity (S') < 10 cm/s, 1 point; right ventricular fractional area change (RVFAC) < 35%, 1 point; and right ventricular myocardial performance index (RV-MPI) > 0.4, 1 point. TAPSE, S', RVFAC, and RV-MPI was 18.7 ± 4.8 mm, 11.9 ± 3.1 cm/s, 33.5 ± 13.9%, and 0.39 ± 0.2, respectively. The RV dysfunction score was associated with symptom [WHO functional class (p = 0.026)], hemodynamics [mean PAP (p = 0.01), cardiac index (p = 0.009), pulmonary vascular resistance (p = 0.001), and SvO (p = 0.039)], exercise capacity [6-min walk distance (p = 0.046), peakVO (p = 0.016), and VE/VCO slope (p = 0.031)], and plasma BNP level (p = 0.005). This RV dysfunction score using the four RV echocardiographic parameters could be a simple and useful scoring system to evaluate prognostic factors in patients with CTEPH.
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http://dx.doi.org/10.1007/s00380-018-1168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133067PMC
October 2018

Left main coronary artery compression by a dilated main pulmonary artery and left coronary sinus of Valsalva aneurysm in a patient with heritable pulmonary arterial hypertension and FLNA mutation.

Pulm Circ 2017 Jul-Sep;7(3):734-740. Epub 2017 Jun 29.

3 Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, Aichi, Japan.

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient's sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A ( FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.
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http://dx.doi.org/10.1177/2045893217716107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841897PMC
June 2017

Circulatory power and ventilatory power over time under goal-oriented sequential combination therapy for pulmonary arterial hypertension.

Pulm Circ 2017 Apr-Jun;7(2):448-454. Epub 2017 Mar 21.

3 Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation-CO production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE-5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg·min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline ( P = 0.047); VP was greater after three months than at baseline ( P = 0.019) and further improved at six months compared with three months ( P = 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal-oriented treatment for PAH.
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http://dx.doi.org/10.1177/2045893217703954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467935PMC
March 2017

Myocardial contractile reserve predicts left ventricular reverse remodeling and cardiac events in dilated cardiomyopathy.

J Cardiol 2017 Oct 18;70(4):303-309. Epub 2017 Mar 18.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Catecholamine sensitivity estimated using a dobutamine stress test (DST) is recognized as a measure of the beta-adrenergic myocardial contractile reserve, which is involved with left ventricular reverse remodeling (LV-RR). We investigated whether the prognostic ability of the DST for LV-RR could predict cardiac events.

Methods: There was a total of 192 enrolled patients with dilated cardiomyopathy (DCM). DCM was defined as a LV ejection fraction (LV-EF) ≤45% and LV end-diastolic dimension (LVDd) ≥55mm. One hundred patients were subjected to micromanometer-based measurement of the maximal first derivative of LV pressure (LVdP/dt), an index of LV contractility, at baseline and following the infusion of dobutamine (10μg/kg/min) via a pigtail catheter. Percentage changes in LVdP/dt from the baseline to peak values under dobutamine stress (ΔLVdP/dt) were also calculated. After excluding 17 patients who received cardiac resynchronization therapy within 3 months of undergoing DST (n=15) and who did not receive follow-up echocardiography (n=2), 83 patients were enrolled (52.5±12.3 years).

Results: During the follow-up period (4.7±2.6 years), LV-RR was recognized in 49 of 83 patients (59.0%). A multivariate logistic regression analysis revealed that ΔLVdP/dt (hazard ratio: 1.024, p=0.007) and the symptom duration (hazard ratio: 0.977, p=0.003) were independent predictors of LV-RR. A receiver operating characteristic curve analysis revealed a ΔLVdP/dt cut-off value of 75.1% for LV-RR and a significantly lower cardiac event rate in the ΔLVdP/dt≥75.1% group (p=0.045).

Conclusions: ΔLVdP/dt estimated using DST was a useful predictor of LV-RR and cardiac events in patients with DCM.
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http://dx.doi.org/10.1016/j.jjcc.2017.02.005DOI Listing
October 2017

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy.

Circ J 2017 Feb 23;81(3):368-375. Epub 2016 Dec 23.

Department of Cardiology, Nagoya University Graduate School of Medicine.

Background: The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dt) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient's prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern.

Conclusions: The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.
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http://dx.doi.org/10.1253/circj.CJ-16-1007DOI Listing
February 2017

Magnetic resonance imaging of cardiac sarcoidosis: an evaluation of the cardiac segments and layers that exhibit late gadolinium enhancement.

Nagoya J Med Sci 2016 Dec;78(4):437-446

Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Cardiac sarcoidosis (CS) can cause sudden death, which is the leading cause of mortality in patients with sarcoidosis in Japan. However, it is difficult to diagnose CS because of the lack of a sensitive diagnostic method for the condition. Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging demonstrates improved sensitivity for diagnosing CS. Therefore, it is important to know the late gadolinium-enhancement (LGE) characteristics of CS on cardiac MR images in order to diagnose CS accurately. In this study, we investigated the most common sites of LGE on cardiac MR images in CS. Late gadolinium-enhanced MR images of 9 consecutive patients with CS (obtained between August 2009 and July 2015) were reviewed by two radiologists. The distribution of LGE was evaluated using the American Heart Association 17-segment model of the left ventricle. The LGE in each segment was also classified into 4 patterns according to the myocardial layer in which it occurred (the subepicardial, subendocardial, intramural, and transmural layer patterns). All 9 patients exhibited LGE in their left ventricle, and 70 of 153 (46%) myocardial segments were enhanced. All of the patients displayed LGE in the basal septal wall. The patients' LGE layer patterns were as follows: subepicardial: 40% (28/70), intramural: 30% (21/70), subendocardial: 16% (11/70), and transmural: 14% (10/70). The basal septum wall and subepicardial layer often exhibit LGE on cardiac MR images in CS patients. LGE can be observed in other segments and layers in some cases.
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http://dx.doi.org/10.18999/nagjms.78.4.437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159469PMC
December 2016

Abnormal Circadian Blood Pressure Profile as a Prognostic Marker in Patients with Nonischemic Dilated Cardiomyopathy.

Cardiology 2017;136(1):1-9. Epub 2016 Aug 19.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: An abnormal circadian blood pressure (BP) profile is considered a risk factor for cardiovascular disease. However, its significance in heart failure patients with nonischemic etiology is unknown. Herein, we investigated the prognostic value of a circadian BP profile in patients with nonischemic dilated cardiomyopathy (NIDCM).

Methods: We enrolled 114 NIDCM patients (76 males, mean age 53.1 years). The percent nighttime BP fall (%NBPF) was defined using ambulatory BP monitoring as a percent decrease in mean systolic BP in nighttime from daytime. All patients were divided into three groups: dipper (%NBPF ≥10), non-dipper (0 ≤ %NBPF < 10), and riser (%NBPF <0).

Results: Riser patients had the highest serum creatinine levels (dipper, 0.78 ± 0.20 mg/dl; non-dipper, 0.85 ± 0.21 mg/dl; riser, 0.99 ± 0.23 mg/dl; p = 0.006). In survival analysis, riser patients had the highest cumulative cardiac-related deaths (log-rank, p = 0.001), which was an independent predictor of cardiac-related deaths (hazard ratio, 12.6; 95% confidence interval, 1.76-253; p = 0.01). Multivariate analysis revealed that the norepinephrine level at 24-hour collected urine (24 h U-NE) and the serum creatinine level were independent determinants of %NBPF (adjusted R2 = 0.20; 24 h U-NE, p = 0.0001; serum creatinine, p = 0.04).

Conclusions: The riser profile was associated with poor prognosis of NIDCM, which may reflect impaired sympathetic nervous system activity. Evaluating the circadian BP profile may be useful for risk stratification in NIDCM patients.
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http://dx.doi.org/10.1159/000446868DOI Listing
August 2018

Ortner's syndrome caused by pulmonary arterial hypertension associated with mixed connective tissue disease.

Clin Exp Rheumatol 2016 Nov-Dec;34(6):1125. Epub 2016 Jul 26.

Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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June 2017

Endomyocardial radial strain rate imaging during dobutamine stress echocardiography for the evaluation of contractile reserve in patients with dilated cardiomyopathy.

J Clin Ultrasound 2016 Nov 14;44(9):555-560. Epub 2016 Jul 14.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: Myocardial contractile reserve is associated with clinical prognosis in patients with dilated cardiomyopathy (DCM). We assessed myocardial contractile reserve using tissue Doppler strain rate imaging with dobutamine stress echocardiography in DCM patients.

Methods: Simultaneous echocardiography and left ventricular (LV) catheterization during dobutamine stress were performed in 20 patients with DCM, and echocardiography was performed in 31 control subjects. Dobutamine was infused at a starting dose of 5 μg/kg/min for 5 minutes and then at 10 μg/kg/min. Peak endomyocardial radial strain (ɛ) and systolic strain rate (SR ) measured with echocardiography and the maximum first derivative of LV pressure (LV dP/dt ) derived from catheterization were used as indices of contractility. Their percentage change from baseline to the dose of 10 μg/kg/min was calculated.

Results: The ɛ and SR were significantly smaller in DCM patients than in controls. The LV dP/dt , ɛ, and SR were significantly higher at the dose of 10 μg/kg/min than at baseline. The percentage change in SR was significantly correlated with the percentage change in LV dP/dt .

Conclusions: Strain rate imaging during dobutamine stress in DCM might prove noninvasively informative for the evaluation of myocardial contractile reserve and provide insight into LV systolic dysfunction. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:555-560, 2016.
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http://dx.doi.org/10.1002/jcu.22376DOI Listing
November 2016

Effects of bosentan on peripheral endothelial function in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

Pulm Circ 2016 Jun;6(2):168-73

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Endothelin receptor antagonists (ERAs) have been shown to improve the prognosis of patients with pulmonary arterial hypertension (PAH). However, the effect of the oral dual ERA bosentan on peripheral endothelial dysfunction (PED), as assessed by flow-mediated vasodilation (FMD), in patients with pulmonary hypertension is not well characterized. We investigated the effect of bosentan on PED in patients with PAH or inoperable chronic thromboembolic pulmonary hypertension (CTEPH). A total of 18 patients with PAH and 8 with CTEPH were treated with bosentan. All patients underwent FMD assessment before and after 3 months of bosentan treatment. Whereas FMD increased from 6.01% ± 2.42% at baseline to 8.07% ± 3.18% after 3 months (P < 0.0001) in patients with PAH, those with CTEPH showed no change in FMD after bosentan therapy. In addition, FMD at baseline showed no correlation with pulmonary vascular resistance (r = 0.09) or plasma brain natriuretic peptide levels (r = -0.23) in patients with PAH. Bosentan treatment ameliorated PED in patients with PAH but not in those with inoperable CTEPH. In addition, FMD did not correlate with PAH severity.
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http://dx.doi.org/10.1086/685715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869920PMC
June 2016

Cardiopulmonary Exercise Testing as a Tool for Diagnosing Pulmonary Hypertension in Patients with Dilated Cardiomyopathy.

Ann Noninvasive Electrocardiol 2016 May 1;21(3):263-71. Epub 2016 Feb 1.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Recently, it has become increasingly recognized that pulmonary hypertension (PH) is a particularly threatening result of left-sided heart disease. However, there have been few investigations of the impact of cardiopulmonary exercise testing (CPX) variables on PH in dilated cardiomyopathy (DCM). We evaluated the usefulness of crucial CPX variables for detecting elevated pulmonary arterial pressure (PAP) in patients with DCM.

Methods: Ninety subjects with DCM underwent cardiac catheterization and CPX at our hospital. Receiver operator characteristic (ROC) analysis was performed to assess the ability of CPX variables to distinguish between the presence and absence of PH.

Results: Overall mean values were: mean PAP (mPAP), 18.0 ± 9.6 mmHg; plasma brain natriuretic peptide, 233 ± 295 pg/mL; and left ventricular ejection fraction, 30.2 ± 11.0%. Patients were allocated to one of two groups on the basis of mean PAP, namely DCM without PH [mean PAP (mPAP) <25 mmHg; n = 75] and DCM with PH (mPAP ≥25 mmHg; n = 15). A cutoff achieved percentage of predicted peak VO2 (%PPeak VO2 ) of 52.5% was the best predictor of an mPAP ≥25 mmHg in the ROC analysis (area under curve: 0.911). In the multivariate analysis, %PPeak VO2 was the only significant independent predictor of PH (Wald 6.52, odds ratio 0.892, 95% CI 0.818-0.974; P = 0.011).

Conclusions: %PPeak VO2 was strongly associated with the presence of PH in patients with DCM. Taken together, these findings indicate that CPX variables could be important for diagnosing PH in patients with DCM.
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http://dx.doi.org/10.1111/anec.12308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931611PMC
May 2016

The Roles of Classic and Current Prognostic Factors in Pulmonary Hypertension Due to Left Heart Disease.

Circ J 2016 8;80(1):72-3. Epub 2015 Dec 8.

Departments of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine.

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http://dx.doi.org/10.1253/circj.CJ-15-1241DOI Listing
August 2016

Epigenome-wide association study suggests that SNPs in the promoter region of RETN influence plasma resistin level via effects on DNA methylation at neighbouring sites.

Diabetologia 2015 Dec 24;58(12):2781-90. Epub 2015 Sep 24.

Department of Genome Science, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan.

Aims/hypothesis: To investigate epigenetic regulation of the plasma concentration of resistin, we performed an epigenome-wide association study for this variable and DNA methylation (DNAm) in an elderly Japanese cohort and then assessed the relation of single nucleotide polymorphisms (SNPs) associated with the plasma resistin concentration to DNAm level at identified sites.

Methods: The association of plasma resistin level with DNAm status was examined in 191 nondiabetic elderly men with the Illumina Infinium HumanMethylation450 BeadChip array. The association between DNAm status at specific sites in the flanking region of the resistin gene (RETN) and RETN mRNA abundance was then evaluated with a public data set for 1202 monocyte samples from a multi-ethnic cohort. Finally, the association of DNAm status and SNPs in the promoter region of RETN was assessed in two cohorts comprising a total of 478 Japanese individuals.

Results: DNAm status at cg02346997 located in the RETN promoter region showed a negative genome-wide significant association with the plasma resistin level (p = 6.02 × 10(-10)). Four DNAm sites in the RETN promoter region including cg02346997 (p = 4.23 × 10(-70)) showed a negative genome-wide significant association with RETN mRNA abundance in monocytes. Furthermore, the number of minor alleles of the RETN promoter SNPs rs34861192 and rs3219175 was negatively associated with DNAm level at cg02346997 (p = 4.43 × 10(-17)).

Conclusions/interpretation: Our results suggest that RETN promoter SNPs might influence the circulating resistin level through an effect on DNAm at cg02346997 and on RETN mRNA abundance in monocytes.
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http://dx.doi.org/10.1007/s00125-015-3763-9DOI Listing
December 2015

Clinical Characteristics and Long-Term Outcomes of Hypertrophic Cardiomyopathy.

Int Heart J 2015 18;56(4):415-20. Epub 2015 Jun 18.

Department of Cardiology, Fujita Health University Banbuntane-Hotokukai Hospital.

Hypertrophic cardiomyopathy (HCM) has various morphological and clinical features. A decade has passed since the previous survey of the epidemiological and clinical characteristics of Japanese HCM patients. The Aichi Hypertrophic Cardiomyopathy (AHC) Registry is based on a prospective multicenter observational study of HCM patients. The clinical characteristics of 42 ambulant HCM patients followed up for up to 5 years were investigated. The primary endpoint was major adverse cardiac events (MACE), defined as death, non-fatal stroke, admission due to congestive heart failure (CHF), or episodes of sustained ventricular tachycardia/fibrillation. The MACE-free survival during the 5-year follow-up period was 76% according to Kaplan-Meier analysis. HCM-related death occurred in 3 (7%) patients and SCD occurred in 2 (5%) patients. Additionally, 3 (7%) patients were admitted to the hospital due to CHF. Meanwhile, sustained VT was detected in one (2%) of the patients who received ICD implantation and subsequently terminated with antitachycardia pacing using an ICD. The patients with HCM exhibiting left ventricular outflow obstruction (HOCM) had a slightly lower MACE-free survival rate than those with neither HOCM nor dilated-HCM (dHCM) (71% versus 81%, log-rank P = 0.581). Furthermore, the patients with dHCM demonstrated a significantly lower MACE-free survival rate than those with neither HOCM nor dHCM (33% versus 81%, log-rank P = 0.029). In the AHC Registry targeting current Japanese HCM patients, we demonstrated that many HCM patients continue to suffer from MACE despite the development of various treatments for HCM.
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http://dx.doi.org/10.1536/ihj.14-418DOI Listing
September 2015

A Successful Case of a Patient Undergoing Warfarin and S-1 Therapy Using Internet-based Control of Home-measured PT-INR.

Yakugaku Zasshi 2015 24;135(7):925-7. Epub 2015 Apr 24.

School of Pharmacy, Aichi Gakuin University.

  To avoid major bleeding events in warfarin and S-1 combination therapy, PT-INR levels should be monitored frequently to allow for precise adjustments of the warfarin dose and to verify any side effects reported by the patient. We therefore developed a support system where outpatients obtain a home-measured PT-INR value using the CoaguChek(®) system and submit it along with details of any side effects to us via the Internet using their mobile phone. A 59-year-old man was started on warfarin (1.5 mg/d) and S-1 (100 mg/d), a combination preparation of tegafur, gimeracil, and oteracil potassium, to treat cholangiocarcinoma. The patient sent his data to the hospital pharmacist every two days after starting S-1 therapy. When the PT-INR was outside the target range of 1.5-2.7, the pharmacist, after consulting the physician, instructed the patient to change his warfarin dose by 0.5 mg. On day 24 after starting S-1, PT-INR had increased from 1.6 to 2.8, so the dose was decreased by 0.5 mg. Thereafter, the dose was adjusted by 0.5-1.0 mg during the observation period so that the patient was able to maintain the therapeutic range approximately 90% of the time. We anticipate this system can be applied to S-1 which interact with warfarin, thereby enabling safer anticoagulation therapy.
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http://dx.doi.org/10.1248/yakushi.15-00016DOI Listing
September 2016

Impact of preoperative regular physical activity on postoperative course after open abdominal aortic aneurysm surgery.

Heart Vessels 2016 Apr 11;31(4):578-83. Epub 2015 Feb 11.

Department of Cardiology, Nagoya Graduate School of Medicine, Nagoya, Japan.

Early ambulation after open abdominal aortic aneurysm (AAA) surgery is assumed to play a key role in preventing postoperative complications and reducing hospital length of stay. However, the factors predicting early ambulation after open AAA surgery have not yet been sufficiently investigated. Here, we investigated which preoperative and intraoperative variables are associated with start time for ambulation in patients after open AAA surgery. A total of 67 consecutive patients undergoing open AAA surgery were included in the study [male, 62 (92 %); mean age, 68 years (range, 47-82 years), mean AAA diameter, 53 mm (range, 28-80 mm)]. Preoperative physical activity was examined by means of 6-min walk distance (6MWD) and a medical interview. Patients were divided into two groups, according to when independence in walking was attained: early group <3 days (n = 36) and late group ≥3 days (n = 31), and the pre-, intra-, and postoperative recovery data were compared. There were no significant differences in patient baseline characteristics or intraoperative data between the two groups. The number of patients engaging in preoperative regular physical activity and 6MWD were significantly greater (p = 0.042 and p = 0.034, respectively) in the early group than in the late group. In addition, time to hospital discharge was significantly shorter in the early group than in the late group (p = 0.031). Binary logistic regression analysis showed that preoperative regular physical activity was the only independent factor for identifying patients in the early group (odds ratio 2.769, 95 % confidence interval 1.024-7.487, p = 0.045). These results suggest that engaging in regular physical activity is an effective predictor of early ambulation after open AAA surgery.
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http://dx.doi.org/10.1007/s00380-015-0644-6DOI Listing
April 2016

Assessment of respiratory disturbance index determined with a non-restrictive monitor and of autonomic nervous system parameters in heart failure patients: A pilot study.

J Cardiol 2015 Sep 3;66(3):218-23. Epub 2015 Feb 3.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: There is a link between sympathetic overactivity and sleep-disordered breathing (SDB), and both of which are important indicators of the development of heart failure. To manage the increasing numbers of heart failure patients, any method used to check for them needs to be as non-invasive, simple, and cost-effective as possible. The purpose of this study is to assess screening of SDB with a non-restrictive monitor and the autonomic nervous system in heart failure patients.

Methods: The subjects were 49 patients (mean age: 67 years; male: 78%) hospitalized for worsening heart failure. After stabilization with appropriate medical therapy, each patient simultaneously underwent sleep apnea syndrome (SAS) screening with the SD-101 (Kenzmedico Co. Ltd., Saitama, Japan), which is a novel, non-restrictive, sheet-like monitor for SAS screening, and assessment of heart rate variability (HRV) with a Holter monitor. In addition, we assessed daytime sleepiness by using the Epworth Sleepiness Scale.

Results: The mean respiratory disturbance index (RDI) was 21.9 events/h. Males had significantly greater RDI values than females (24.5±11.2 events/h vs. 13.0±6.2 events/h, p<0.001). RDI on SD-101 testing was closely correlated with cyclic variation of heart rate index obtained with a Holter electrocardiogram scanner (r=0.843). Although plasma brain natriuretic peptide level was not correlated with HRV, plasma norepinephrine level was moderately well correlated with the total low- to high-frequency ratio of HRV (r=0.529).

Conclusions: SAS screening is important for heart failure patients, because absence of subjective sleepiness is not reliable in ruling out SDB. The SAS screening with SD-101 might apply for managing heart failure.
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http://dx.doi.org/10.1016/j.jjcc.2014.12.018DOI Listing
September 2015

Prognostic impact of combined late gadolinium enhancement on cardiovascular magnetic resonance and peak oxygen consumption in ambulatory patients with nonischemic dilated cardiomyopathy.

J Card Fail 2014 Nov 21;20(11):825-32. Epub 2014 Aug 21.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Peak oxygen consumption (peak VO₂) and late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) are prognostic in heart failure. We investigated whether LGE-CMR and peak VO₂combined had additive value in risk stratifying patients with nonischemic dilated cardiomyopathy (DCM).

Methods And Results: Fifty-seven DCM patients underwent CMR and cardiopulmonary exercise testing. Cardiac events were cardiac death, hospitalization for decompensated heart failure, or lethal arrhythmia. Twenty-five (44%) were LGE-positive. The median peak VO₂was 18.5 mL·kg(-1)·min(-1). On multivariate analysis, positive LGE (P = .048) and peak VO₂(P = .003) were independent cardiac event predictors. Cardiac event risk was significantly higher with positive LGE and peak VO₂< 18.5 mL ·kg⁻¹ ·min⁻¹ than with negative LGE and peak VO₂≥ 18.5 mL · kg⁻¹ · min⁻¹ (hazard ratio 12.5; 95% CI 1.57-100; P = .017). In 3 patient groups (group A: no LGE, peak VO₂≥ 18.5 mL · kg⁻¹ · min⁻¹, n = 18; group B: positive LGE or peak VO₂< 18.5 mL · kg⁻¹ · min⁻¹, n = 24; group C: positive LGE and peak VO₂< 18.5 mL · kg⁻¹ · min⁻¹, n = 15) during follow-up (71 ± 32 months), group C had higher cardiac event rates than the others.

Conclusions: Combined assessment of LGE-CMR and peak VO₂provides additive prognostic information in ambulatory DCM.
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http://dx.doi.org/10.1016/j.cardfail.2014.08.005DOI Listing
November 2014

Combination therapy adding tadalafil to existing ambrisentan in patients with pulmonary arterial hypertension.

Hypertens Res 2014 Jun 20;37(6):488-9. Epub 2014 Mar 20.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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http://dx.doi.org/10.1038/hr.2014.37DOI Listing
June 2014

Cardiopulmonary exercise testing to evaluate the exercise capacity of patients with inoperable chronic thromboembolic pulmonary hypertension: an endothelin receptor antagonist improves the peak PETCO2.

Life Sci 2014 Nov 15;118(2):397-403. Epub 2014 Mar 15.

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan. Electronic address:

Aims: The 6-min walking distance is often used for assessing the exercise capacity under the treatment with an endothelin receptor antagonist (ERA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The cardiopulmonary exercise testing (CPX) was reported to be more useful for the patients with pulmonary arterial hypertension (PAH), however, few reports exist in patients with inoperable CTEPH. The aim of this study was to investigate the effects of an oral dual ERA, bosentan, on exercise capacity using CPX in patients with PAH and inoperable CTEPH.

Main Methods: This study included all patients diagnosed with 17 PAH and 12 CTEPH in the World Health Organization functional classes II-IV who started treatment with bosentan therapy. They underwent CPX, which was performed before bosentan therapy and at 3 to 6 months of the treatment.

Key Findings: In PAH patients, peak VO2 significantly increased after the bosentan treatment (p=0.009). On the other hand, in CTEPH patients, there were no significant differences in the peak VO2. However, the peak PETCO2 was significantly increased from 23.9±5.2 mm Hg at baseline to 29.3±10.7 mm Hg after the bosentan treatment (p=0.040). In addition, peak heart rate during exercise tended to decrease after the bosentan therapy (p=0.089).

Significance: Bosentan therapy improved peak PETCO2 but not peak VO2 in patients with inoperable CTEPH. These findings demonstrated that CPX is useful for assessing the exercise capacity of patients with PAH and inoperable CTEPH under the treatment with an ERA.
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http://dx.doi.org/10.1016/j.lfs.2014.03.009DOI Listing
November 2014

Imatinib is partially effective for the treatment of pulmonary capillary hemangiomatosis.

Intern Med 2014 ;53(6):603-7

Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.

A 43-year-old man presented with dyspnea on exertion. Right heart catheterization demonstrated pulmonary arterial hypertension (PAH). He was treated with bosentan, sildenafil and intravenous epoprostenol. Despite the administration of such intensive therapy, the patient's condition deteriorated to a World Health Organization functional class (WHO-FC) of IV. He participated in a clinical trial of imatinib for PAH. After three months of treatment with imatinib, the chest X-ray and echocardiography findings improved, and the WHO-FC class was III. One year after, however, the PAH worsened again, and the patient died 2.6 years after the first diagnosis. At autopsy, patchy capillary proliferation was observed in the lungs. The definitive diagnosis was pulmonary capillary hemangiomatosis.
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http://dx.doi.org/10.2169/internalmedicine.53.1157DOI Listing
May 2015

Prognostic factors in pulmonary arterial hypertension with Dana Point group 1.

Life Sci 2014 Nov 13;118(2):404-9. Epub 2014 Mar 13.

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. Electronic address:

Aims: To clarify the prognosis and prognostic factors in pulmonary arterial hypertension (PAH) patients in real-world medical practice in the Tokai area in Japan.

Main Methods: We conducted a retrospective, multicenter observational study. The data of 81 patients diagnosed with Dana Point group 1 or 1' PAH was collected from January 2005 to January 2013. The primary outcome was all-cause death.

Key Findings: The patients consisted of 34 cases of idiopathic PAH (IPAH), 28 of connective tissue-associated PAH (CTD-PAH), 16 of congenital heart disease-associated PAH (CHD-PAH) and others. Mean age was 51 years and mean observation period was 46 months. The systolic blood pressure (BPs) was 117±23 mm Hg. Pericardial effusion was observed in 27.0% of patients. The mean right atrial pressure (mRAP) was 10.2±7.3 mm Hg. In the univariate Cox regression analysis, WHO-FCS III & IV, a cardiac index (CI)<2.5 L/min/m(2), and the presence of pericardial effusion at baseline were significantly associated with all-cause death. In the multivariate analysis, the pericardial effusion (HR 3.3, 95% CI 1.03-10.63, p=0.04) and mRAP (HR 3.2, 95% CI 1.03-9.83, p=0.04) or CI<2.5 L/min/m(2) (HR 3.89, 95% CI 1.05-14.45, p=0.04) were the independent predictors of mortality.

Significance: The presence of pericardial effusion and mRAP or CI<2.5 L/min/m(2) at diagnosis indicated high mortality.
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http://dx.doi.org/10.1016/j.lfs.2014.03.002DOI Listing
November 2014

Prognostic value of pulmonary hypertension in ambulatory patients with non-ischemic dilated cardiomyopathy.

Circ J 2014 13;78(5):1245-53. Epub 2014 Mar 13.

Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine.

Background: Pulmonary hypertension (PH) because of left-sided heart disease carries a poor prognosis. We investigated whether non-ischemic dilated cardiomyopathy (DCM) with PH is associated with poor prognosis.

Methods And Results: A total of 256 consecutive DCM patients were enrolled. We measured the ratio of the maximum first derivative of left ventricular pressure (LVdP/dtmax)/systolic blood pressure and pressure half-time (T1/2) as cardiac function. Patients were allocated to 2 groups on the basis of mean pulmonary arterial pressure (mPAP), namely DCM without PH group (mPAP <25 mmHg; n=225) and DCM with PH group (mPAP ≥25 mmHg; n=31). We followed all patients for a mean of 4.3 years for the occurrence of cardiac events, defined as cardiac death or hospitalization for worsening heart failure. Cardiac events were significantly more frequent in the DCM with PH group than in the DCM without PH group (P<0.001). Multivariate Cox regression analysis revealed that mPAP ≥25 mmHg and LV end-systolic volume index were significant independent risk factors for cardiac death. Incidence of cardiac death was significantly higher in patients with DCM with PH than in those without PH [hazard ratio 11.79 (3.18-43.7), P<0.0001].

Conclusions: The presence of PH was independently associated with an increased incidence of cardiac death in ambulatory patients with DCM.
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http://dx.doi.org/10.1253/circj.cj-13-1120DOI Listing
August 2015

Recovery of flow-mediated vasodilatation after repetitive measurements is involved in early vascular impairment: comparison with indices of vascular tone.

PLoS One 2014 2;9(1):e83977. Epub 2014 Jan 2.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879271PMC
November 2014
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