Safety and Efficacy of Long-Term Use of Tolvaptan in Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow-up duration was 1.6 years (1.0-4.4 years).Methods and Results:One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan. CONCLUSIONS: In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions.

Impact of red blood cell distribution width on non-cardiac mortality in patients with acute decompensated heart failure with preserved ejection fraction.

BACKGROUND: The prognostic impact of red blood cell distribution width (RDW) on adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. We investigated the association between RDW values at admission and long-term prognosis in patients with acute decompensated HFpEF. METHODS: The present study enrolled 278 consecutive patients with acute decompensated HFpEF, whose RDW levels were measured at admission. We divided enrolled patients into 2 groups according to RDW value and investigated the association between RDW and patients' mortality. RESULTS: A Kaplan-Meier analysis demonstrated that patients with higher RDW levels had significantly higher all-cause and non-cardiac mortality, but not cardiac-based mortality, than did patients with lower RDW levels. A multivariate Cox regression analysis revealed that RDW levels were independently correlated with all-cause and non-cardiac mortality after adjusting for other risk factors, including age, brain natriuretic peptide, hemoglobin, and Charlson comorbidity index score. In a receiver-operating curve analysis, the cut-off value to maximize the prognostic impact of RDW on mortality was 15.2%. The evaluation of RDW and other prognostic factors improved their predictive value for both all-cause and non-cardiac mortality. CONCLUSIONS: The current study demonstrated that RDW levels at admission independently predict poor outcomes because of non-cardiac events in patients with acute decompensated HFpEF. Evaluation of RDW could provide useful information for the long-term prognosis of HFpEF.

Early Spontaneous Remission of Intramyocardial Dissecting Hematoma.

Intramyocardial dissecting hematoma is a rare but potentially fatal complication of myocardial infarction. The decision to adopt a surgical or conservative strategy may depend on the clinical and hemodynamic stability of patients. Regardless, the precise and temporal assessment of the structure of hematoma is imperative. We herein report the first case of a patient with early spontaneous remission of intramyocardial dissecting hematoma successfully managed by a conservative approach with multimodality imaging.

Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction.

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011-1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.

Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease.

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m(2)). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan-Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.

Elevation of red blood cell distribution width during hospitalization predicts mortality in patients with acute decompensated heart failure.

BACKGROUND: Increased red blood cell distribution width (RDW) is associated with adverse outcomes in heart failure. In the present study, we assessed the association between changes in RDW values during hospitalization and long-term prognosis in patients with acute decompensated heart failure (ADHF). METHODS: We measured the RDW value in 229 consecutive patients with ADHF. Blood samples were obtained at the time of hospital admission and at discharge. Changes in RDW were calculated as the mean difference between RDW values on admission and those at the time of hospital discharge. RESULTS: Patients were followed up for a median of 692 days. A Kaplan-Meier survival analysis demonstrated that patients whose RDW levels increased during hospitalization had significantly higher all-cause and cardiac-based mortality following heart failure than did patients whose RDW levels decreased during hospitalization. A multivariate Cox regression analysis revealed that change in RDW values during hospitalization, but not the values of RDW and hemoglobin on admission, was independently correlated with all-cause and cardiac-based mortality after adjusting for other risk factors in patients with ADHF. CONCLUSIONS: These data document that the change in RDW values during hospitalization independently predicts poor outcomes in patients with ADHF. Continuous follow-up of RDW values could provide useful information for long-term prognosis after heart failure.

Impact of sitagliptin on carotid intima-media thickness in patients with coronary artery disease and impaired glucose tolerance or mild diabetes mellitus.

Sitagliptin has been widely used for the treatment of diabetes and shown recently to have beneficial pleiotropic outcomes on cardiovascular systems in experimental studies. However, little is known about the influence of sitagliptin on atherosclerosis-related cardiovascular diseases in a clinical setting. This study examined the effect of sitagliptin on carotid intima-media thickness (IMT). A total of 76 patients with clinically stable and documented coronary artery disease, who were newly diagnosed with impaired glucose tolerance or mild type 2 diabetes mellitus, were allocated, randomly, to receive either sitagliptin 100 mg/day or the placebo control. Common carotid IMT, glucose profiles, glycosylated hemoglobin (HbA1c), and lipid profiles were measured at baseline and repeated at 12 months. Sitagliptin-treated patients showed less IMT progression than the control group (p = 0.02). In addition, the sitagliptin group showed greater reductions in body weight (2.2%), 2-hour glucose levels on the 75-g oral glucose tolerance test (17.3%), HbA1c (4.7%), and low-density lipoprotein cholesterol levels (7.9%) from that at baseline. In conclusion, treatment with sitagliptin for 12 months was associated with a beneficial effect in the prevention of carotid IMT progression, compared with the diet control.

Serum albumin levels predict clinical outcomes in chronic kidney disease (CKD) patients undergoing cardiac resynchronization therapy.

OBJECTIVE: A low level of serum albumin is common in chronic kidney disease (CKD) patients with heart failure (HF). Cardiac resynchronization therapy (CRT), a novel therapeutic option, improves cardiac performance in patients with severe HF. In addition, CKD has recently been found to be associated with outcomes after CRT; however, the associations of the serum albumin levels with adverse events and the long-term prognosis in CKD patients who have undergone CRT are unknown. In this study, we investigated whether the albumin levels can be used to the predict mortality rate and incidence of cardiovascular events in CKD patients treated with CRT. METHODS: A retrospective chart review was conducted in 102 consecutive CKD patients receiving a CRT device for the treatment of advanced HF. The long-term outcomes following device implantation were assessed according to the albumin levels. RESULTS: During a median follow-up of 2.6 years, 34 patients (33.3%) died and 66 patients (64.7%) experienced cardiovascular events. A Kaplan-Meier survival analysis revealed that the CKD patients with decreased albumin levels exhibited significantly higher rates of all-cause mortality and cardiovascular events, including hospitalization for progressive HF, than the CKD patients without hypoalbuminemia. Importantly, a multivariate Cox regression analysis of confounding factors showed a low serum albumin level to independently predict all-cause death and cardiovascular events. CONCLUSION: Hypoalbuminemia independently predicts cardiac morbidity and mortality in CKD patients receiving CRT. Assessing the albumin levels provides valuable information regarding the long-term prognosis in CKD patients who undergo CRT.

Novel transitional zone index allows more accurate differentiation between idiopathic right ventricular outflow tract and aortic sinus cusp ventricular arrhythmias.

BACKGROUND: Although several ECG algorithms have been proposed for differentiating the origins of outflow tract ventricular arrhythmia (OT-VA), their accuracy still is limited in cases with cardiac rotation. OBJECTIVE: The purpose of this study was to assess whether a novel "cardiac rotation-corrected" transitional zone (TZ) index would be a useful marker for differentiating right ventricular outflow tract (RVOT) origin from aortic sinus cusp (ASC) origin. METHODS: Surface ECGs of OT-VAs with left bundle branch block morphology and inferior axis in 112 patients who were successfully ablated in the RVOT (n = 87) or the ASC (n = 25) were analyzed. The TZ index was defined according to the site of R-wave transition of sinus beats and OT-VAs. RESULTS: The TZ index was significantly lower in the ASC origin than in the RVOT origin (-1.2 ± 0.9 vs 0.3 ± 0.7, P <.0001). A cutoff value of the TZ index <0 predicted the ASC origin with 88% sensitivity and 82% specificity. The previously reported R-wave duration index ≥ 50% had a high specificity of 85% but a low sensitivity of 44%, and R/S-wave amplitude index ≥ 30% had 68% sensitivity and 79% specificity. The area under the curve by receiver operating characteristic curve analysis was 0.90 for the TZ index, which was significantly higher than the R-wave duration index and R/S-wave amplitude index of 0.74 and 0.76, respectively. CONCLUSION: This novel TZ index can be a more useful marker for differentiating RVOT origin from ASC origin.

Combined assessment of left ventricular dyssynchrony and contractility by speckled tracking strain imaging: a novel index for predicting responders to cardiac resynchronization therapy.

BACKGROUND: Mechanical dyssynchrony is an important factor in the response to cardiac resynchronization therapy (CRT). However, no echocardiographic measure can improve prediction of case selection for CRT. OBJECTIVE: The purpose of this study was to assess the efficacy of a newly combined echocardiographic index for ventricular dyssynchrony and contractility using speckled tracking strain analysis to predict responders to CRT. METHODS: Forty-seven patients with severe heart failure in New York Heart Association functional class III/IV, left ventricular ejection fraction /=130 ms were included in the study. Echocardiography was performed, and a novel index (i-Index), the product of radial dyssynchrony and radial strain, was calculated. Responder to CRT was defined as a patient with a >/=15% decrease in left ventricular end-systolic volume at 6-month follow-up. RESULTS: Thirty-two patients (68%) were classified as responders. The i-Index was significantly higher in responders than in nonresponders (3,450 +/- 1180 vs 1,481 +/- 841, P <.001). The area under receiver operator characteristic curve was 0.92 for the i-Index, which was better than the index of radial dyssynchrony only (0.74). A cutoff value of i-Index >2,000 predicted responders with 94% sensitivity and 80% specificity. The index using only radial dyssynchrony had 81% sensitivity and 53% specificity. Furthermore, i-Index decreased in responders (1,985 +/- 1261, P <.001) but not in nonresponders (1,684 +/- 866, P = .48). CONCLUSION: Our findings suggest that a novel combined index by radial strain echocardiography might be a predictor of response to CRT. The value of this novel echocardiographic index requires further assessment in larger studies.

Normalisation of plasma growth hormone levels improved cardiac dysfunction due to acromegalic cardiomyopathy with severe fibrosis.

A 51-year-old man was referred to the Department of Cardiology in our hospital due to severe congestive heart failure and ventricular arrhythmias in March 2008. He had repeated ventricular tachycardia for years and the left ventricular ejection fraction (EF) was 11% on admission. A myocardial biopsy revealed that over 50% cardiomyocytes were replaced by fibrosis. Due to the typical acromegalic features, he was referred to the endocrinology department and diagnosed as acromegaly. He was treated with octreotide for 8 months followed by trans-sphenoidal surgery. The plasma levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) decreased by octreotide and normalised by surgery after which the cardiac function improved drastically. The current case demonstrates that cardiac dysfunction in acromegaly could be recovered by normalisation of GH and IGF-1 even in the presence of severe fibrosis in the myocardium.

Morphological characteristics of the Holter P-waves associated with pulmonary vein pacing.

AIMS: Identification of arrhythmogenic pulmonary veins (PVs) initiating atrial fibrillation is helpful for catheter ablation. The aim of this study was to examine the possibility to recognize the arrhythmogenic PV using Holter ECG. METHODS AND RESULTS: In 20 patients, P-wave characteristics were studied during pacing from four PVs. Holter ECG was recorded using two leads: the modified CC5 (Lead 1) and NASA (Lead 2), and the P-wave amplitude and duration were evaluated. In Lead 1, P-waves produced by left PV pacing were significantly lower in amplitude than right PV pacing (-3 +/- 75 vs. 86 +/- 43 microV, P < 0.001). In Lead 2, pacing in superior PVs produced P-waves with higher amplitude than inferior PVs (210 +/- 74 vs. 125 +/- 66 muV, P < 0.001). The criteria proposed by the morphological characteristics of P-waves identified putative arrhythmogenic PVs with an accuracy of 78%. CONCLUSION: It might be possible to identify putative arrhythmogenic PVs by modified Holter ECG recording.

Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation.

BACKGROUND: Oxidative stress is associated with atrial fibrillation (AF). However, little is known about the relationship between serum markers of oxidation and electrical activity in patients with AF. OBJECTIVE: The purpose of this study was to investigate the possible association between serum markers of reactive oxidative metabolism and atrial remodeling in paroxysmal and persistent AF. METHODS: Derivatives of reactive oxidative metabolites (DROM), an index of oxidative stress, were measured in 306 consecutive patients with AF (225 paroxysmal, 81 persistent) undergoing radiofrequency (RF) catheter ablation. Filtered P-wave duration by P-wave signal-averaged ECG and levels of high-sensitivity C-reactive protein (CRP) as an inflammatory marker also were measured. RESULTS: Patients were followed up for 1.2 +/- 0.8 years. DROM levels in patients with persistent AF were significantly higher than in patients with paroxysmal AF (341.6 +/- 85.5 Carratelli [Carr] units vs 305.0 +/- 77.7 Carr units, P <.001). DROM levels showed a tighter, positive correlation with filtered P-wave duration in persistent AF patients (r = 0.56, P <.001) than in all AF patients (r = 0.13, P <.05). DROM levels also showed a weaker but significant correlation with high-sensitivity CRP in patients with AF. Kaplan-Meier analysis revealed that the highest quartile of basal DROM levels exhibited a significantly higher AF recurrence rate after RF catheter ablation in patients with paroxysmal AF (P <.01). CONCLUSION: Serum markers of oxidative stress reflect atrial conduction disturbance and predict AF recurrence after RF catheter ablation in paroxysmal AF patients. DROM could serve as a biomarker for predicting risk of AF recurrence after RF catheter ablation.

Circulating homocysteine levels in patients with radiofrequency catheter ablation for atrial fibrillation.

AIMS: This study investigated the potential association between homocysteine levels and cardiovascular events or atrial fibrillation (AF) recurrence following radiofrequency catheter ablation (RFCA) in patients with AF. METHODS AND RESULTS: Blood samples were obtained prior to the RFCA procedure. Levels of homocysteine and carboxy-terminal telopeptide of collagen type I (CITP), a collagen type I degradation marker, were measured in 96 patients receiving RFCA; 62 paroxysmal or persistent AF patients and 34 paroxysmal supra-ventricular tachycardia patients. Patients were followed up for 2.1 +/- 1.5 years. Plasma homocysteine levels were significantly higher in patients with persistent AF (P < 0.05) compared with levels in paroxysmal AF and control patients. Homocysteine levels also positively correlated with left atrial dimension (LAD) (P < 0.01) and CITP levels (P < 0.001). While no significant correlation was found between basal homocysteine levels and recurrent AF after RFCA in AF patients, patients in the high homocysteine group exhibited a significantly higher rate of cardiovascular events without AF recurrence compared with those in the low homocysteine group (P < 0.05). CONCLUSION: High homocysteine levels are associated with the presence of persistent AF, which is accompanied by increased CITP levels and LAD. Also confirmed is the role of homocysteine as a risk factor for the pathogenesis of cardiovascular events after RFCA in AF patients. Measurement of homocysteine level may provide useful information for the managing cardiovascular risk in patients with AF.

Circulating adiponectin levels in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) characterized by atrial remodeling occurs with obesity-related conditions. Adiponectin, an adipose tissue-derived hormone exerts beneficial effects on ventricular remodeling, so in the present study the potential association between circulating adiponectin levels and atrial remodeling in patients with AF was investigated. METHODS AND RESULTS: The levels of plasma adiponectin, serum carboxy-terminal telopeptide of collagen type I (CITP), as a collagen type I degradation marker, and serum type III procollagen-N-peptide (PIIINP), as a collagen type III synthesis marker, were measured in 304 consecutive patients (162 paroxysmal AF, 46 persistent AF, 96 paroxysmal supra-ventricular tachycardia [controls]). Plasma adiponectin levels were significantly higher in patients with persistent AF than in those with paroxysmal AF or the control patients (p<0.05). Serum CITP levels, but not serum PIIINP levels, were higher in patients with persistent AF compared with the paroxysmal AF and control patients (p<0.05). In addition, there was a positive correlation between adiponectin levels and CITP levels in patients with persistent AF (r=0.39, p<0.005). CONCLUSIONS: High plasma adiponectin levels are associated with the presence of persistent AF, which is accompanied by increased CITP levels. Thus, measurement of plasma adiponectin could be useful for assessment of AF.

Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator pioglitazone antagonizes angiotensin II actions and possesses anti-inflammatory and antioxidant properties in vitro. There is evidence that pioglitazone improves ventricular remodeling in some experimental models. OBJECTIVE: The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure. METHODS: Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses. RESULTS: Atrial fibrillation (AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits (mean duration of AF: 8.0 +/- 1.4 seconds). Pioglitazone reduced the duration of AF (3.5 +/- 0.2 seconds, P <.05) and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 +/- 2 ms vs 41 +/- 2 ms, P <.05) and atrial fibrosis (16.8% +/- 0.8% vs 10.9% +/- 0.7%, P <.05; control 1.6% +/- 0.2%), effects comparable to those of candesartan (duration of AF: 3.0 +/- 0.2 seconds; activation time 44 +/- 2 ms; fibrosis: 9.4% +/- 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-beta1, tumor necrosis factor-alpha, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone. CONCLUSION: Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR-gamma may be a potential therapeutic target for human AF.

Reduction of early elastic recoil by cutting balloon angioplasty as compared to conventional balloon angioplasty.

BACKGROUND: Restenosis after successful balloon angioplasty remains problematic. Early elastic response after angioplasty is significant when considering the possible development of restenosis. The purpose of this study was to compare early elastic recoil within 10 minutes after successful percutaneous transluminal coronary angioplasty and early lumen loss at 24 hours after angioplasty in a cutting balloon group and a conventional balloon group. METHODS: Extent of early elastic recoil was quantitatively measured as the difference of mean balloon diameter at maximal inflation pressure and minimal luminal diameter after angioplasty in 82 cutting balloon-treated lesions and 51 conventional balloon-treated lesions. RESULTS: Reference diameter and balloon/artery ratio were similar between the cutting balloon and conventional balloon groups (2.89 0.47 mm vs. 2.88 0.60 mm; 1.19 0.11 vs. 1.19 0.13, respectively). Early elastic recoil after angioplasty was significantly smaller in the cutting balloon than the conventional balloon group (0.96 0.40 mm vs. 1.12 0.37 mm, respectively; p = 0.04). Also, the mean amount of lumen loss from 10 minutes after angioplasty to 24 hours after was significantly smaller in the cutting balloon than the conventional balloon group (0.08 0.28 mm vs. 0.20 0.33 mm, respectively; p = 0.02). CONCLUSION: There is significantly less early elastic recoil in the cutting balloon angioplasty than in the conventional balloon angioplasty group. The efficacy of cutting balloon continues 24 hours after angioplasty.