Shunsuke Tamaki

Cardiac Iodine-123 Metaiodobenzylguanidine Imaging Predicts Sudden Cardiac Death Independently of Left Ventricular Ejection Fraction in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction: Results From a Comparative Study With Signal-Averaged Electrocardiogram, Heart Rate Variability, and QT Dispersion

OBJECTIVES We prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG), heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF). BACKGROUND Cardiac MIBG imaging predicts prognosis of CHF patients. However, the long-term predictive value of MIBG imaging for SCD in this population remains to be elucidated. METHODS At entry, cardiac MIBG imaging, SAECG, 24-h Holter monitoring, and standard 12-lead electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients with a radionuclide left ventricular ejection fraction (LVEF) <40%. The cardiac MIBG washout rate (WR) was obtained from MIBG imaging. Furthermore, the time and frequency domain HRV parameters were calculated from 24-h Holter recordings, and QT dispersion was measured from the 12-lead ECG. RESULTS During a follow-up period of 65 +/- 31 months, 18 of 106 patients died suddenly. A multivariate Cox analysis revealed that WR and LVEF were significantly and independently associated with SCD, whereas the SAECG, HRV parameters, or QT dispersion were not. Patients with an abnormal WR (>27%) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95% confidence interval: 1.55 to 14.76). Even when confined to the patients with LVEF >35%, SCD was significantly more frequently observed in the patients with than without an abnormal WR (p = 0.02). CONCLUSIONS Cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.

Prediction of sudden death in patients with mild-to-moderate chronic heart failure by using cardiac iodine-123 metaiodobenzylguanidine imaging

Objective: To evaluate the usefulness of cardiac iodine-123 (123I) metaiodobenzylguanidine (MIBG) imaging as a predictor of sudden death in patients with chronic heart failure (CHF). Design and setting: Prospective cohort study in a tertiary referral centre. Patients: 97 outpatients with CHF with a radionuclide left ventricular ejection fraction <40% (mean (SD) 29% (7.5%)). Interventions: At study entry, cardiac I-123 MIBG imaging was performed. The cardiac MIBG heart-to-mediastinum ratio (H/M) and washout rate (WR) were obtained from MIBG imaging. Main outcome measures: Patients were assigned to two groups based upon 27% of WR, which was the mean (2SD) control WR. 48 of 97 patients with CHF had abnormal WR (⩾27%), whereas the remaining 49 patients had normal WR (<27%). All the study patients were then followed up. Results: During the mean (SD) follow-up period of 65 (29) months, 12 (25%) patients in the abnormal WR group and 2 (4%) patients in the normal WR group died suddenly. Kaplan–Meier analysis revealed that sudden death was more often observed in patients with abnormal WR than those with normal WR (p = 0.001). On Cox regression analysis, MIBG WR, H/M on the delayed image and H/M on the early image were significantly associated with sudden death. Conclusion: Cardiac MIBG imaging would be useful for predicting sudden death in patients with CHF.

L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease

Objectives: Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. Methods and results: Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. Conclusions: L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

Ca2+ entry mode of Na+/Ca2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction

AIMS Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na(+)/K(+)-ATPase and activate the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. METHODS AND RESULTS (i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague-Dawley rats. (iii) Ouabain elevated intracellular Ca(2+) concentration through the entry of extracellular Ca(2+), increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced (3)H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening. CONCLUSION Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Competing risks of heart failure with preserved ejection fraction in diabetic patients

The prevalence of heart failure with preserved ejection fraction (HFpEF) has increased in the past two decades, and diabetes mellitus (DM) is frequently associated with HFpEF. Although it has been demonstrated that left ventricular (LV) diastolic and vascular functional abnormalities are generally observed in HFpEF, it remains to be clinically elucidated how an asymptomatic stage progresses to symptomatic HFpEF in DM patients. We aimed to identify risk factors associated with incident HFpEF in DM patients and to evaluate the contribution of LV relaxation and compliance to the development of HFpEF.

Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction

Background Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. Methods and Results An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. Conclusion Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Usefulness of Cardiac Iodine-123 Meta-Iodobenzylguanidine Imaging to Improve Prognostic Power of Seattle Heart Failure Model in Patients With Chronic Heart Failure

The Seattle Heart Failure Model (SHFM) is a validated prediction model that estimates the mortality in patients with chronic heart failure (CHF) using commonly obtained information, including clinical data, laboratory test results, medication use, and device implantation. In addition, cardiac iodine-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information for patients with CHF. However, the long-term predictive value of combining the SHFM and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac iodine-123 MIBG imaging provides additional prognostic value to the SHFM in patients with CHF, we studied 106 outpatients with CHF who had radionuclide left ventricular ejection fraction < 40% (30 ± 8%). The SHFM score was obtained at enrollment, and the cardiac MIBG washout rate (WR) was calculated from anterior chest images obtained at 20 and 200 minutes after isotope injection. During a mean follow-up of 6.8 ± 3.5 years (range 0 to 13), 32 of 106 patients died from cardiac causes. A multivariate Cox analysis revealed that the WR (p = 0.0002) and SHFM score (p = 0.0091) were independent predictors of cardiac death. Kaplan-Meier analysis showed that patients with an abnormal WR (> 27%) had a significantly greater risk of cardiac death than did those with a normal WR for both those with a SHFM score of ≥ 1 (relative risk 3.3, 95% confidence interval 1.2 to 9.7, p = 0.01) and a SHFM score of ≤ 0 (relative risk 3.4, 95% confidence interval 1.2 to 9.6, p = 0.004). In conclusion, the cardiac MIBG WR provided additional prognostic information to the SHFM score for patients with CHF.

A novel heart failure mice model of hypertensive heart disease by angiotensin II infusion, nephrectomy, and salt loading

Although the mouse heart failure (HF) model of hypertensive heart disease (HHD) is useful to investigate the pathophysiology and new therapeutic targets for HHD, the model using simple experimental procedures and stable phenotypes has not been established. This study aimed to develop a novel mouse HF model of HHD by combining salt loading and uninephrectomy with ANG II infusion. Eight-week-old C57BL/6 male mice were treated with ANG II infusion (AT), ANG II infusion and uninephrectomy (AN), ANG II infusion and salt loading (AS), or ANG II infusion, uninephrectomy, and salt loading (ANS). Systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was found in AT, AN, AS, and ANS mice, and there were no significant differences in those parameters between the four groups. At 6 wk after the procedures, only ANS mice showed significant decreases in LV fractional shortening and increases in lung weight with a high incidence. This phenotype was reproducible, and there were few perioperative or early deaths in the experimental procedures. Severe LV fibrosis was found in ANS mice. Oxidative stress was enhanced and small GTPase Rac1 activity was upregulated in the hearts of ANS mice. After the addition of salt loading and uninephrectomy to the ANG II infusion mouse model, cardiac function was significantly impaired, and mice developed HF. This might be a novel and useful mouse HF model to study the transition from compensated LV hypertrophy to HF in HHD.

Long-term β-blocker therapy improves diastolic function even without the therapeutic effect on systolic function in patients with reduced ejection fraction

The beneficial effects of beta-blocker therapy on the clinical outcomes of heart failure with reduced ejection fraction (HFREF) are attributed to the improvement in ejection fraction (EF) and left ventricular (LV) reverse remodeling. Previous studies only reported the beta-blocker therapy-induced improvement of diastolic function accompanied by the increase in EF in HFREF patients. This retrospective study aimed to elucidate whether beta-blocker therapy improves diastolic function even without an increase in EF. Out of the consecutive 11,830 echocardiographic reports, HFREF patients without an increase in EF following long-term beta-blocker therapy comprised the study subjects (n=19). During the mean follow-up of 17 months, beta-blocker therapy significantly decreased peak mitral E-wave velocity (70±25-50±18 cm/s, p<0.01) and ratio of peak mitral E- to A-wave velocities (E/A ratio) (1.4±0.8-0.9±0.4, p<0.05), prolonged deceleration time of the mitral E-wave velocity (DcT) (167±54-206±61 ms, p<0.05), and improved New York Heart Association functional class (2.3±0.7-1.8±0.4, p<0.01) without changes in LV volume. Because DcT and E/A ratio are well known to correlate with LV filling pressures in patients with reduced EF, our results indicate a reduction in LV filling pressures without changes in LV volume, suggesting a reduction in LV stiffness. Thus, long-term beta-blocker therapy is likely to improve diastolic function even without a concomitant increase in EF in HFREF patients, which may be also responsible for the beta-blocker-induced improvement of their symptoms of heart failure.

Tolvaptan Reduces the Risk of Worsening Renal Function in Patients With Acute Decompensated Heart Failure and Preserved Left Ventricular Ejection Fraction - Prospective Randomized Controlled Study.

BACKGROUND Although the mainstay of treatment for acute decompensated heart failure (ADHF) is decongestion by diuretic therapy, it is often associated with worsening renal function (WRF). The effect of tolvaptan, a selective V2 receptor antagonist, on WRF in ADHF patients with preserved left ventricular ejection fraction (LVEF) is unknown.Methods and Results:We enrolled 50 consecutive ADHF patients whose LVEF on admission was ≥45%. Patients were randomly assigned to either tolvaptan add-on (n=26) or conventional diuretic therapy (n=24). The primary endpoint was the incidence of WRF, defined as an increase in serum creatinine (Cr) ≥0.3 mg/dL or 50% above baseline within 48 h of randomization. There was no significant difference between the 2 groups in the change in body weight or the total urine volume during 48 h. However, the change in Cr (∆Cr) at 24 and 48 h after randomization and the incidence of WRF (12% vs. 42%, P=0.0236) were significantly lower, and the fractional excretion of urea (FEUN) at 24 and 48 h after randomization was significantly higher in the tolvaptan group. There was an inverse correlation between ∆Cr and FEUN at 48 h after randomization. CONCLUSIONS Tolvaptan can alleviate congestion with a significantly lower risk of WRF in ADHF patients with preserved LVEF, presumably through maintenance of renal perfusion.