Effects of Additive Tolvaptan vs. Increased Furosemide on Heart Failure With Diuretic Resistance and Renal Impairment　- Results From the K-STAR Study.

BACKGROUND: Although diuretic resistance leading to residual congestion is a known predictor of a poorer heart failure (HF) prognosis, better therapeutic strategies for effective and safe decongestion have not been established.Methods and Results:In this study, 81 HF patients with fluid retention (despite taking ≥40 mg/day furosemide (FUR)), with an estimated glomerular filtration rate <45 mL/min/1.73 m2, were randomized into 2 groups and administered either ≤15 mg/day additive tolvaptan (TLV) or ≤40 mg/day increased FUR for 7 days. Changes in urine volume between baseline and mean urine volume during treatment were significantly higher in the TLV than FUR group (P=0.0003). Although there was no significant decrease in body weight or improved signs and symptoms of congestion between the 2 groups, the increase in serum creatinine on Day 7 from baseline was significantly smaller in the TLV than FUR group (P=0.038). Multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% confidence interval 0.043-0.605, P=0.001) was an independent clinical factor for improved renal function during treatment compared with increased FUR. CONCLUSIONS: In HF patients with residual congestion and renal dysfunction refractory to standard therapy, additive TLV increased urine volume without further renal impairment compared with patients who received an increased dose of FUR.

Prognostic significance of beta-blocker up-titration in conjunction with cardiac resynchronization therapy in heart failure management.

Clinical practice guidelines emphasize that optimal pharmacotherapy, including beta-blockers (BB), is a prerequisite before receiving cardiac resynchronization therapy (CRT) in eligible patients with heart failure (HF). However, the optimal dose of BB before CRT implantation cannot be tolerated in a number of patients. Sixty-three consecutive patients who underwent CRT in 2006-2013 were retrospectively investigated. Before receiving CRT, BB could not be introduced in 20 patients (32 %); the daily carvedilol-equivalent dose in other 43 patients was 5.6 ± 7.0 mg because of significant HF and bradycardia. After receiving CRT, BB could be introduced in almost all patients (n = 61, 97 %), and the daily BB dose increased from 5.6 ± 7.0 to 13.2 ± 7.8 mg (P < 0.001). Multivariate analysis indicated that the change of BB dose after CRT was independently associated with improved left ventricular end-systolic volume (LVESV) [ß = -0.36; 95 % confidence interval (CI) -2.13 to -0.45; P < 0.01] after 6-months follow-up. Furthermore, Cox proportional hazard analysis also showed that the change in the BB dose (hazard ratio, 0.92; 95 % CI, 0.87-0.98; P < 0.01) as well as the New York Heart Association functional classification was an independent predictor of cardiac events. After initiating CRT, BB therapy can be introduced and up-titrated in intolerant HF patients. The up-titrated dose of BB after CRT was an independent predictor for the improvement of LVESV and HF prognosis.

Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin.

Myocardial infarction (MI) leads to necrosis and uncontrolled release of cellular content. Binucleated and polyploid cardiomyocytes contain high amounts of chromatin, a DNA polymer of histones which are cytotoxic. We hypothesized that chromatin from necrotic cells accumulates in the non-perfused, ischemic infarct region, causing local high concentrations of cytotoxic histones, thereby potentiating damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion which could lead to a decrease in local histone concentrations and cytotoxicity. It was confirmed that after permanent coronary artery ligation in mice, extracellular histones accumulated within the infarcted myocardium. In vitro, histones caused myocyte cytotoxicity. For protection against histone-mediated cytotoxicity after MI in vivo, DNase1 was administered within the first 6 h after induction. Indeed, DNase1 accumulation in the infarcted region of the heart was observed, as well as effective disruption of extracellular cytotoxic chromatin and subsequent reduction of high local histone concentrations. Functionally, acute DNase1 treatment resulted in significantly improved left ventricular remodeling in mice as measured by serial echocardiography, while mortality, infarct size and inflammatory parameters were unaffected. Notably, improved cardiomyocyte survival within the infarct region was observed and might account for the protective effects in acutely DNase1-treated animals. Disruption of extracellular cytotoxic chromatin within the infarcted heart by acute DNase1 treatment is a promising approach to protect myocytes from histone-induced cell death and subsequent left ventricular dysfunction after MI.

Cellular immunity and cardiac remodeling after myocardial infarction: role of neutrophils, monocytes, and macrophages.

Today, innate immunity is recognized as an important pathophysiologic factor and therapeutic target for cardiac remodeling after myocardial infarction (MI). The innate immune system exerts its function via soluble and cellular components. Recently, function and kinetics of immune cells after MI have been clarified using new innovative technology. Therefore, herein, we will discuss the function of neutrophils, monocytes, and macrophages in the pathophysiology of cardiac remodeling after MI in basic as well as clinical science.

Clinical significance of heart rate during acute decompensated heart failure to predict left ventricular reverse remodeling and prognosis in response to therapies in nonischemic dilated cardiomyopathy.

Although an increased heart rate (HR) is a strong predictor of poor prognosis in cases of chronic heart failure (HF), the clinical value of HR as a predictor in acute decompensated HF (ADHF) is unclear. Seventy-eight patients with nonischemic dilated cardiomyopathy (NIDCM) with sinus rhythm who were first hospitalized for ADHF from 2002 to 2010 were retrospectively investigated after exclusion of patients with tachycardia-induced cardiomyopathy. The patients were divided into two groups stratified by HR on admission with a median value of 113 beats/min (Group H with HR ≥ 113 beats/min; Group L with HR < 113 beats/min). Despite similar backgrounds, including pharmacotherapy for HF, HR changes responding to titration of ß-blocker (BB) therapy and myocardial interstitial fibrosis, left ventricular (LV) ejection fractions improved more significantly 1 year later in Group H than in Group L (57 % ± 11 % vs. 46 % ± 12 %, P < 0.001). Cardiac event-free survival rates were also significantly improved in Group H (P = 0.038). Multiple regression analysis revealed that only the peak HR on admission was an independent predictor of LV reverse remodeling (LVRR) 1 year later (ß = 0.396, P = 0.005). High HR on first admission for ADHF is a strong predictor of LVRR, with a better prognosis in the event of NIDCM in response to optimal pharmacotherapy, independent of pre-existing myocardial damage and subsequent HR reduction by BB therapy.

Baseline cardiac magnetic resonance imaging versus baseline endomyocardial biopsy for the prediction of left ventricular reverse remodeling and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy.

Endomyocardial biopsy (EMB) and late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging performed at baseline are both used to evaluate the extent of myocardial fibrosis. However, no study has directly compared the effectiveness of these diagnostic tools in the prediction of left ventricular reverse remodeling (LVRR) and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Seventy-five patients with newly diagnosed IDCM who were undergoing optimal therapy were assessed at baseline using LGE-CMR imaging and EMB; the former measured LGE area and the latter measured collagen volume fraction (CVF) as possible predictive indices of LVRR and cardiac event-free survival. Among all the baseline primary candidate factors with P < 0.2 as per univariate analysis, multivariate analysis indicated that only LGE area was an independent predictor of subsequent LVRR (ß = 0.44; 95 % confidence interval (CI) 0.87-2.53; P < 0.001), as indicated by decreasing left ventricular end-systolic volume index over the 1-year follow-up. Kaplan-Meier curves indicated significantly lower cardiac event-free survival rates in patients with LGE at baseline than in patients without (P < 0.01). By contrast, there was no significant difference in prognosis between patients with CVF values above (severe fibrosis) and below (mild fibrosis) the median of 4.9 %. Cox proportional hazard analysis showed that LGE area was an independent predictor of subsequent cardiac events (hazard ratio 1.06; 95 % CI 1.02-1.10; P ≤ 0.01). The degree of myocardial fibrosis estimated by baseline LGE-CMR imaging, but not that estimated by baseline EMB, can predict LVRR and cardiac event-free survival in response to therapy in patients with newly diagnosed IDCM.

Two-week interval optical coherence tomography: imaging evidence on neointimal coverage completion after implantation of the Endeavor zotarolimus-eluting stent.

OBJECTIVE: To obtain imaging evidence by 2-week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus-eluting stent (E-ZES). BACKGROUND: Despite the fact that NIC is a cardinal process in the pathomechanism of late stent thrombosis, little imaging information is available on morphological changes thereof on a short-time interval basis. METHODS: 27 Japanese patients with stable angina pectoris and de novo native coronary artery lesions were enrolled, and 27 lesions (30 implantations) were examined. OCT was performed at weeks 2, 4, 6, 8, and 10 after E-ZES implantation. NIC was examined using cross-sectional OCT images obtained at the 1.0-mm intervals. RESULTS: In total, 621 cross-sectional OCT images, which depicted 7,747 stent struts, were analyzed. The mean percentages of stent strut coverage at weeks 2, 4, 6, 8, and 10 after E-ZES implantation were 12.3, 70.4, 67.9, 86.0, and 99.2%, respectively; a marked increase was found between weeks 2 and 4. The mean thicknesses of the formed neointima were 40.2, 52.1, 48.1, 86.5, and 146.2 µm at respective weeks, with the high-signal and thick neointima (146 µm) at week 10. An intracoronary thrombus was detected in only one stent at week 4. CONCLUSIONS: The full circumferential coverage of the vessel wall by the high-signal neointima was found at as early as week 10 after E-ZES implantation, imparting a surrogate index for vascular healing by NIC.

Clinical significance of corticosteroid therapy for eosinophilic myocarditis.

The recommended treatment for eosinophilic myocarditis (EM), pathologically defined as myocardial inflammation with eosinophil infiltration, is corticosteroids. Although EM has a wide variety of clinical features including the degree of eosinophilic infiltration, there have been no reports on how patients with EM should be treated with corticosteroids irrespective of their pathological findings.Thirty-seven consecutive patients with acute myocarditis hospitalized in our institute between 1996-2009 were enrolled. Excluding those with secondary EM such as Loeffler's endocarditis, hypereosinophilic syndrome, and Churg-Strauss Syndrome, together with drug-induced allergic myocarditis, the subjects were divided into 2 groups according to the existence of eosinophils in the myocardial interstitium observed in endomyocardial biopsy specimens. There were no differences in the clinical characteristics on admission between the 2 groups: with (group EM, n = 22) and without (group lymphocytic myocarditis (LM), n = 7) eosinophilic infiltrates irrespective of pathological differences. The treatment policy has been consistent in our institution: intensive hemodynamic observation and support without corticosteroid administration, not only in LM but also in idiopathic EM. There was no significant difference in clinical recovery in the acute phase as indicated by the hospitalization period, left ventricular ejection fraction, or long-term prognosis in EM compared to LM.A conventional management strategy for idiopathic EM without corticosteroid administration can improve the prognosis in the acute and chronic phases, similar to that of LM.

Comparison of nitrite compounds and carperitide for initial treatment of acute decompensated heart failure.

Human atrial natriuretic peptides and nitrite compounds (NC) are infused for the initial management of acute heart failure (HF). However, there have been few studies comparing their hemodynamic effects.Fifty-two patients in acute decompensated HF (ADHF) who received carperitide (0.07 ± 0.05 µg/kg/minute, n = 23, group C) or NC (0.39 ± 0.24 µg/kg/minute, n = 29, group N) during the initial 24 hours in the intensive care unit between 1997 and 2007 were studied. We measured and compared hemodynamic parameters by pulmonary artery catheter monitoring before and after drug administration. Heart rate (HR), diastolic pulmonary artery pressure (DPAP), and central venous pressure (CVP) after the 24-hour administration were lower (HR: 92 ± 18 versus 79 ± 13 bpm, DPAP: 17 ± 6 versus 11 ± 5 mmHg, CVP: 6 ± 4 versus 3 ± 3 mmHg, P < 0.05, respectively) and the reduction of DPAP and systemic vascular resistance index were higher in group N than in group C. However, there was no significant difference regarding other indicators of preload and afterload. Although the serum B-type natriuretic peptide (BNP) level at discharge was lower in group N than group C (382 ± 434 versus 207 ± 201 pg/mL, P < 0.05), there was no significant difference in either the in-hospital reduction of BNP, the duration of hospitalization, or total cardiac events during 1-year follow-up.Although NC tended to improve the hemodynamics of ADHF more than carperitide, both drugs had a similar prognostic impact in patients with ADHF.

Prognostic significance of right ventricular dimension on acute decompensation in chronic left-sided heart failure.

Right ventricular (RV) dysfunction has been discussed in relation to an adverse outcome in heart failure (HF). The aim of this study was to analyze the relationship between RV function with HF exacerbation and its subsequent long-term outcome in patients with chronic left-sided HF.We studied 122 consecutive patients who were admitted for dyspnea due to exacerbated left-sided HF with a left ventricular (LV) ejection fraction of less than 40%. Conventional echocardiography was performed in the study subjects on admission and at discharge. Cox proportional hazards analysis revealed that RV end-diastolic dimension (RVDd) (hazard ratio 1.131, P = 0.005, 95% confidence interval 1.039-1.231) and the serum level of creatinine on admission were independent predictors of subsequent cardiac-related death, but RVDd at discharge and other LV parameters were not. Thus, patients were divided into tertiles on the basis of RVDd on admission: < 32 mm (n = 37), 32-40 mm (n = 43), and ≥ 40 mm (n = 42). According to the increase in the RVDd category, the cardiac-related death-free rate significantly decreased. Among the 3 groups, the pulse pressure and serum total bilirubin levels that demonstrated low cardiac output syndrome (LOS) parameters had significant differences.RVDd on admission could be measured noninvasively and easily to predict a worse long-term prognosis of chronic left-sided HF on admission, and showed correlations with LOS parameters.

Effect of hypothermia therapy after outpatient cardiac arrest due to ventricular fibrillation.

BACKGROUND: Several investigators have emphasized the positive effect of hypothermia therapy on patients who have suffered from cardiac arrest. Salvaging patients from circulatory collapse is a pivotal task, but it is unclear whether additional hypothermia can practically contribute to an improvement in the neurological outcome. METHODS AND RESULTS: Since December 2005, our hospital has been using hypothermia therapy. Forty-six comatose patients after recovery of spontaneous circulation were consecutively enrolled in the present study. Twenty-five of the enrolled patients received hypothermia therapy and 21 did not because they were treated prior to 2005. The time from collapse to spontaneous circulation (P=0.09), the rates of performance of bystander CPR (P=0.370) and presence of a witnessed collapse (P=0.067) were not significantly different between the recovery group (n=28) and the non-recovery group (n=18). The additional hypothermia therapy was an independent predictor of neurological recovery (P=0.005, OR 6.5, 95%CI 1.74-24.27). The recovery rate was significantly higher in patients who received hypothermia therapy (80%) compared to those who did not (38%). CONCLUSIONS: Hypothermia therapy is very useful for treating patients who have had an out-of-hospital cardiac arrest; it should be induced rapidly and smoothly.

Beta2-Adrenergic agonists suppress rat autoimmune myocarditis: potential role of beta2-adrenergic stimulants as new therapeutic agents for myocarditis.

BACKGROUND: The therapeutic potential of beta2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure-induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. METHODS AND RESULTS: Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the beta2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-gamma mRNA levels. Propranolol, a nonselective beta-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a beta1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin-primed lymph node cells from drug-treated rats. In vitro addition of beta2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a beta2-selective AR antagonist. Furthermore, treatment with 2 different beta2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. CONCLUSIONS: beta2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin-specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. beta2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.

The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia.

We investigated the lipid lowering and anti-atherosclerotic effects of atorvastatin in patients with hypercholesterolemia. Thirty patients were given atorvastatin 10 mg daily, and assessed for serum lipids, intima-media thickness (IMT), and brachial-ankle pulse wave velocity (ba-PWV) at the baseline, 6 months, and 12 months. Remnant-like particle-cholesterol (RLP-C), lipoprotein (a)(Lp(a)), and high-sensitivity C-reactive protein (hs-CRP) were measured in some patients at the baseline and at 6 months. Total cholesterol, triglyceride and low-density lipoprotein cholesterol were significantly decreased by 32%, 23% and 44% at 6 months, respectively, and these effects were sustained at 12 months. There was no change in high-density lipoprotein cholesterol. IMT at the baseline was 0.88 +/- 0.16 mm and decreased to 0.76 +/- 0.13 mm at 6 months, remaining at 0.75 +/- 0.12 mm at 12 months. We did not observe any significant changes in ba-PWV. RLP-C and hs-CRP were significantly reduced from 7.3 +/- 10.8 mg/dL to 4.3 +/- 5.3 mg/dL and 0.075 +/- 0.065 mg/dL to 0.039 +/- 0.043 mg/dL at 6 months, respectively. There was no change in Lp(a). The observed decrease in IMT suggests that atorvastatin possibly improves atherosclerosis, in addition to the significant reduction of serum lipids.

A case of aortic bicuspid valve with thrombus formation without severe stenosis and calcification.

We encountered a patient with a history of juvenile cerebral infarction with an unknown cause in whom a mass adhering to the aortic valve (AV) surface was observed on echocardiography performed upon the development of heart failure. Mild AV stenosis (AS) with moderate regurgitation was noted, and valve repair was applied. It was found during surgery that the AV was a bicuspid valve (BAV) without calcification, and the mass was an organized thrombus. Thrombus formation on the AV with severe AS in BAV has been reported, but the organic lesion in the AV was mild in this patient.

Hemodialysis is an independent predictor of coronary in-stent restenosis after paclitaxel eluting stent implantation.

OBJECTIVE: A drug eluting stent is often used for high-risk patients with complications such as diabetes mellitus (DM) and hemodialysis (HD), however the factors to predict restenosis after paclitaxel-eluting stent (PES) placement have not been reported to date. METHODS: Between May 2007 and August 2009, 165 consecutive patients (231 stents) received PES in our hospital. Stent diameter and length were determined by the use of intravascular ultrasound (IVUS). All patients continued to take 2 types of anti-platelet agents (aspirin and Clopidogrel or Ticlopidine). Ninety percent of the subjects received a follow-up coronary angiogram 6 months later. RESULTS: Underlying diseases were hypertension in 75%, hyperlipidemia in 78% and DM in 60% (15% on insulin), and 14% of the subjects received HD. Eighty-three percent of the patients had orally taken Statin, 85% ACE/ARB and 68% had beta blockers. Mean length and diameter of PES were 21.6 ± 7.2 mm and 2.9 ± 0.3 mm, respectively. Target lesion revascularization (TLR) rate 6 months after PES placement was 14.6% overall. In HD patients TLR was 43%, hypertension 15.0%, hyperlipemia 12.4%, DM with oral medication 12.5%, DM with insulin 12.0%, respectively. In multivariate analysis, HD was an independent risk factor for TLR (p=0.0001, OR: 6.61, 95% C.I.: 2.34-18.6). CONCLUSION: HD had the greatest influence on TLR after PES even though risk factors were well controlled. It is necessary to develop new PCI techniques and stents that are useful for HD patients.

End-tidal carbon dioxide concentration can estimate the appropriate timing for weaning off from extracorporeal membrane oxygenation for refractory circulatory failure.

Although extracorporeal membrane oxygenation (ECMO) is widely used as temporary circulation support, there are no reports of direct parameters indicating cardiac recovery to determine the timing of weaning off. Twenty-five patients supported by ECMO due to hemodynamic deterioration were divided into 2 groups according to their outcome: weaned ECMO (W: n = 18) or not (NW: n = 7). In the W group, we examined the differences in parameters between the 2 time points, ECMO introduction, and the reduction in ECMO flow to 40% of the initial setting known as the conventional recovery point (C-point). Significant differences were observed in systolic pulmonary artery pressure, the cardiac index measured by the thermodilution method, C-reactive protein, lactate, base excess, and the end-tidal CO(2) concentration (ETCO(2)). Next, by closely examining these 6 parameters measured every 12 hours, we found that only ETCO(2) had always changed steeply, like a 'flexion point' (E-point), in all W cases, but not in NW. The E-point was defined as an initial increase in ETCO(2) of >or= 5 mmHg over the preceding 12 hours with a continued rise over the next 12 hours. E-points appeared as much as 95 +/- 60 hours earlier than C-points and also preceded weaning off of ECMO. ETCO(2) can be a useful continuous parameter for predicting the adequate timing of weaning off of ECMO for circulatory failure at the bedside.

Clinical impact of adherence to guidelines on the outcome of chronic heart failure in Japan.

The impact of guideline adherence on clinical outcomes in the management of chronic heart failure (CHF) has never been evaluated in Japan. We investigated outcomes in 92 consecutive CHF patients admitted to Kitasato University Hospital in 2004-2006 for HF exacerbation with a left ventricular ejection fraction < or = 40% by the use of class I drugs for pump-failure, as recommended in the Japanese Circulation Society guideline. Drugs, namely angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (BB), spironolactone, diuretics, and cardiac glycosides were administered to 64.1%, 59.8%, 28.2%, 96.7%, and 68.0% of patients, respectively. Patients for whom adherence to the prescription of ACEI and BB as first-line agents was high had significantly and independently better prognostic outcomes for cardiac events (P = 0.0036) as well as subsequent improvements in clinical surrogate markers for HF status such as NYHA class and BNP. Addition of the 3 latter drugs to the prescription of ACEI and BB did not affect the superiority of ACE plus BB in improving the long-term prognosis. We have demonstrated that adherence to treatment guidelines for CHF is a significant predictor of subsequent cardiac events in actual practice in Japan. An effective means of improving adherence to current guideline standards of care for CHF has yet to be established.