Soluble urokinase-type plasminogen activator receptor represents exercise tolerance and predicts adverse cardiac events in patients with heart failure.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a membrane-binding protein that is released into the blood stream by immune activation. Recent reports suggest that circulating suPAR levels are associated with adverse cardiovascular outcomes. Exercise tolerance is an independent predictor of prognosis in patients with heart failure (HF); however, the relationship between serum suPAR level and exercise tolerance is unclear. We prospectively enrolled 94 patients who were hospitalized for worsening of HF. All patients underwent a symptom-limited cardiopulmonary exercise test to evaluate exercise tolerance. The median value of serum suPAR was 4848 pg/ml. During follow up, 44 patients (47%) were admitted for all-cause mortality and re-hospitalization for HF. Median serum suPAR was significantly higher in the patients with cardiac events than in the patients with non-event group. Patients were divided into two groups according to circulating suPAR levels. Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly higher in the high suPAR group (log-rank p = 0.023). Multivariate analysis revealed that suPAR was independently correlated with the parameters of exercise tolerance such as anaerobic threshold (p = 0.007) and peak oxygen uptake (p = 0.005). suPAR levels predicted adverse cardiac events and independently correlated with the parameters of exercise tolerance. suPAR could be a useful surrogate biomarker of exercise tolerance in patients with HF.

Greater Nocturnal Blood Pressure Is Associated With Natriuretic Peptide Level in Aortic Stenosis With Preserved Ejection Fraction.

BACKGROUND: Although careful monitoring of asymptomatic severe aortic stenosis (AS) is recommended to prevent missing the optimal timing of surgical or transcatheter aortic valve replacement, prophylactic treatment that could extend the asymptomatic period remains unknown. In a hypertensive population, high blood pressure (BP) measured at the doctor's office is known to be associated with B-type natriuretic peptide (BNP) level, a surrogate marker for symptomatic deterioration in AS. Little is known regarding the association between nocturnal BP variables and BNP in severe AS with preserved ejection fraction (EF). Methods and Results: The subjects consisted of 78 severe AS patients (mean age, 79±6 years) with preserved EF. Nocturnal BP was measured hourly using a home BP monitoring device. On multiple regression analysis, nocturnal mean systolic BP (SBP) remained independently associated with BNP after adjustment for age, sex, body mass index, estimated glomerular filtration rate, antihypertensive medication class, early diastolic mitral annular velocity, and left ventricular mass index (P=0.03), whereas diastolic BP (DBP) and variables of BP variability were not. CONCLUSIONS: Higher nocturnal SBP rather than DBP or indices of BP variability was independently associated with BNP in AS patients with preserved EF. Intervention for nocturnal SBP may therefore extend the asymptomatic period and improve prognosis.

Serum brain-derived neurotrophic factor level and exercise tolerance complement each other in predicting the prognosis of patients with heart failure.

Brain-derived neurotropic factor (BDNF) is a myokine that plays a key role in regulating survival, growth, and maintenance of neurons. We investigated whether the serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Furthermore, we aimed to examine the relationship between this myokine and exercise tolerance. We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. At discharge, the serum BDNF level of all patients was measured using a commercial ELISA kit and they underwent a cardiopulmonary exercise test to measure peak oxygen uptake (peak VO2). Correlation was not observed between BDNF and peak VO2. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization owing to worsening HF was significantly higher in the low BDNF group (p = 0.023). The combination of peak VO2 and BDNF levels led to the identification of subgroups with significantly different probabilities of events (p = 0.005). In particular, in the low BDNF and low peak VO2 group, the frequency of rehospitalization within half a year after discharge was much higher than that in other groups. Multivariate analysis found BDNF as an independent factor of adverse events (hazard ratio 0.956; 95% confidence interval 0.911-0.999; p = 0.046). The serum BDNF level at discharge may be a useful biomarker of the prognosis in patients with HF. Furthermore, combining BDNF and peak VO2 may be useful for predicting early cardiac events.

Impact of simple electrocardiographic markers as predictors for deterioration of left ventricular function in patients with frequent right ventricular apical pacing.

Several trials demonstrated that frequent right ventricular apical pacing (RVAP) was associated with cardiac dysfunction and an increased rate of heart failure hospitalization. However, there are few reports about the 12-lead electrocardiogram (12-ECG) parameters at the time of device implantation to predict deterioration of LVEF in patients with frequent RVAP. We retrospectively studied 115 consecutive patients undergoing pacemaker or implantable cardioverter-defibrillator implantation with RVAP, with rate of ventricular pacing ≥ 40% and LVEF ≥ 50% at the time of implantation. We compared the 12-ECG characteristics at the time of device implantation between patients with deterioration of LVEF (≥ 10% reduction) and those without. Twenty-nine patients (25%) had deteriorated LVEF with a decrease in mean LVEF from 59 to 40% during a median follow-up period of 8.9 [4.6-13.7] years. Multivariate logistic regression analysis showed that cumulative % of ventricular pacing [odds ratio (OR) 1.04 per 1% increase, 95% confidence interval (CI) 1.01-1.09, p = 0.04], notching of baseline paced QRS in limb leads (OR 5.04, 95% CI 1.59-19.6, p = 0.005) and the QS pattern in all precordial leads (OR 3.56, 95% CI 1.21-10.8, p = 0.02) were independently associated with deterioration of LVEF. The QS pattern of baseline paced QRS in all precordial leads had 58% sensitivity, 93% specificity for the RV lead position at the tip of RV apex. In conclusion, considering OR by multivariate analysis, notching of baseline paced QRS in limb leads and the QS pattern in all precordial leads at device implantation may be simple and useful predictors to identify patients who are at risk for deterioration of cardiac function during long-term RVAP. 12-ECG monitoring at device implantation and avoidance of the RVAP site showing a QS pattern may be important to prevent deterioration of cardiac function in patients with frequent RVAP.

Echocardiographic parameters predicting acute hemodynamically significant mitral regurgitation during transfemoral transcatheter aortic valve replacement.

BACKGROUND: Alteration in mitral valve morphology resulting from retrograde stiff wire entanglement sometimes causes hemodynamically significant acute mitral regurgitation (MR) during transfemoral transcatheter aortic valve replacement (TAVR). Little is known about the echocardiographic parameters related to hemodynamically significant acute MR. METHODS AND RESULTS: This study population consisted of 64 consecutive patients who underwent transfemoral TAVR. We defined hemodynamically significant acute MR as changes in the severity of MR with persistent hypotension (systolic blood pressure < 80-90 mm Hg or mean arterial pressure 30 mm Hg lower than baseline). Hemodynamically significant acute MR occurred in 5 cases (7.8%). Smaller left ventricular end-systolic diameter (LVDs), larger ratios of the coiled section of stiff wire tip to LVDs (wire-width/LVDs), and higher Wilkins score were significantly associated with hemodynamically significant acute MR (P < .05), whereas the parameters of functional MR (annular area, anterior-posterior diameter, tenting area, and coaptation length) were not. Moreover, when patients were divided into 4 groups according to wire-width/LVDs and Wilkins score, the group with the larger wire-width/LVDs and higher Wilkins score improved prediction rates (P < .05). CONCLUSIONS: Small left ventricle or wire oversizing and calcific mitral apparatus were predictive of hemodynamically significant acute MR. These findings are important for risk stratification, and careful monitoring using intraoperative transesophageal echocardiography may improve the safety in this population.

Safety and Efficacy of Simultaneous Biplane Mode of 3-Dimensional Transesophageal Echocardiography-Guided Antegrade Multiple-Inflation Balloon Aortic Valvuloplasty in Patients With Severe Aortic Stenosis.

BACKGROUND: Balloon aortic valvuloplasty (BAV) is resurging as a bridge treatment in patients with severe aortic stenosis (AS) with a dissemination of transcatheter aortic valve implantation. However, the significantly high periprocedural mortality and complication rates still limit the indications of BAV. Further efforts are needed to improve the safety and efficacy of BAV.Methods and Results:We retrospectively investigated the safety and efficacy of simultaneous biplane mode of 3-dimensional transesophageal echocardiography (biplane-TEE) guided antegrade transseptal multiple-inflation BAV, with gradual upsizing of the balloon, by enrolling 20 consecutive AS patients who underwent BAV. The median age was 83 years, and there were 6 male patients (30.0%). The clinical frailty scale was 4, and the Society of Thoracic Surgeon score was 14.5%. The balloon was inflated at a median of 18 times, which improved the mean aortic valve pressure gradient from 43.0 to 15.2 mmHg (P<0.001). We safely performed BAV in all patients, without periprocedural death or symptomatic stroke, although asymptomatic stroke was detected in 8 patients (42.1%) on diffusion-weighted magnetic resonance imaging. Kaplan-Meier estimates showed that the survival rate was 84.0% and cardiovascular death-free survival was 88.9% at 1-year. CONCLUSIONS: Biplane-TEE guided antegrade multiple-inflation BAV might have the potential to improve periprocedural survival without increasing complications, compared with conventional retrograde BAV in patients with severe AS.

Administration of tolvaptan with reduction of loop diuretics ameliorates congestion with improving renal dysfunction in patients with congestive heart failure and renal dysfunction.

In patients with congestive heart failure and renal dysfunction, high dose of diuretics are necessary to improve congestion, which may progress to renal dysfunction. We examined the efficacy of tolvaptan with reduction of loop diuretics to improve renal function in patients with congestive heart failure and renal dysfunction. We conducted a multicenter, prospective, randomized study in 44 patients with congestive heart failure and renal dysfunction (serum creatinine concentration ≥1.1 mg/dl) treated with conventional diuretics. Patients were randomly divided into two groups: tolvaptan (15 mg) with a fixed dose of diuretics or with reducing to a half-dose of diuretics for 7-14 consecutive days. We examined the change of urine volume, body weight, serum creatinine and electrolyte concentrations in each group. Both groups demonstrated significant urine volume increase (724 ± 176 ml/day in the fixed-dose group and 736 ± 114 ml/day in the half-dose group) and body weight reduction (1.6 ± 1.5 kg and 1.6 ± 1.9 kg, respectively) from baseline, with no differences between the two groups. Serum creatinine concentration was significantly increased in the fixed-dose group (from 1.60 ± 0.47 to 1.74 ± 0.66 mg/dl, p = 0.03) and decreased in the half-dose group (from 1.98 ± 0.91 to 1.91 ± 0.97 mg/dl, p = 0.10). So the mean changes in serum creatinine concentration from baseline significantly differed between the two groups (0.14 ± 0.08 mg/dl in the fixed-dose group and -0.07 ± 0.19 mg/dl in the half-dose group, p = 0.006). The administration of tolvaptan with reduction of loop diuretics was clinically effective to ameliorate congestion with improving renal function in patients with congestive heart failure and renal dysfunction.

Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation.

Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy with variable muscular dystrophy. These mutations enhance mitogen-activated protein kinase signaling in the heart and pharmacological inhibition of extracellular signal-regulated kinase (ERK) 1 and 2 improves cardiac function in Lmna(H222P/H222P) mice. In the current study, we crossed mice lacking ERK1 to Lmna(H222P/H222P) mice and examined cardiac performance and survival. Male Lmna(H222P/H222P)/Erk1(-/-) mice lacking ERK1 had smaller left ventricular end systolic diameters and increased fractional shortening (FS) at 16 weeks of age than Lmna(H222P/H222P/)Erk1(+/+) mice. Their mean survival was also significantly longer. However, the improved cardiac function was abrogated at 20 weeks of age concurrent with an increased activity of ERK2. Lmna(H222P/H222P)/Erk1(-/-) mice treated with an inhibitor of ERK1/2 activation had smaller left ventricular diameters and increased FS at 20 weeks of age. These results provide genetic evidence that ERK1 and ERK2 contribute to the development of cardiomyopathy caused by LMNA mutations and reveal interplay between these isoenzymes in maintaining a combined pathological activity in heart.

Higher visit-to-visit intra-dialytic blood pressure is associated with the progression of aortic valve stenosis in chronic hemodialysis patients.

Aortic valve stenosis (AS) is a frequent complication contributing to poor prognosis in chronic hemodialysis (CHD) patients. High blood pressure (BP) is known to be associated with AS progression in the general population. In CHD patients, however, BP varies during and between hemodialysis sessions with ultrafiltration volume or inter-dialytic weight gain; therefore it is difficult to characterize the BP status with a conventional single measurement. Our purpose was to clarify the BP variables affecting AS progression in CHD patients. We retrospectively enrolled 32 consecutive CHD patients with AS [aortic valve area (AVA), 1.3 ± 0.3 cm(2); mean age 69 ± 8 years] who had serial transthoracic echocardiographic studies at least 6 months apart (mean 23 ± 9 months). AS progression was evaluated using absolute reduction in AVA per year. Pre-dialytic and intra-dialytic (every hour during sessions) BPs throughout the 3 consecutive visits were used to determine each patient's BP status. We calculated the mean values of pre-dialytic and intra-dialytic BPs and their variability. In univariate analysis, mean visit-to-visit pre-dialytic and intra-dialytic BP were associated with AS progression, whereas all variables of BP variability were not. Multiple regression analysis indicated that only mean visit-to-visit intra-dialytic systolic and diastolic BP remained independently associated with AS progression after adjustment for age, sex, hypertension, hypercholesterolemia, diabetes mellitus, and serum parathyroid hormone (p < 0.05). Although BP regulation in CHD patients is complex and multifactorial, mean visit-to-visit intra-dialytic BP was independently associated with AS progression. Prospective studies are necessary before considering intra-dialytic BP as a potential target for therapy.

Four cases of investigational therapy with interleukin-11 against acute myocardial infarction.

We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients.