Pirfenidone (5-methyl-1-phenyl-2-(1)H-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated ...whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg(-1) min(-1)) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg(-1) per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-β1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.
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 VO
2
). Correlation was not observed between BDNF and peak VO
2
. 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 VO
2
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 VO
2
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 VO
2
may be useful for predicting early cardiac events.
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.
Background:
Myocardial fractional flow reserve (FFR) is useful in the evaluation of coronary lesion ischemia. However, the impact of lesion length on FFR has not been adequately assessed.
Hypothesis:
...We hypothesized that lesion length would influence functional significance in intermediate coronary lesions.
Methods:
FFR measurements were assessed in 136 patients (163 lesions) with stable angina who had >40% stenotic coronary lesion by quantitative coronary angiography (QCA). One hundred sixty‐three lesions were classified as intermediate (40%–70% stenosis; n=107; group I) or significant (≥70%; n=56; group S) by QCA. We assessed the relationships between lesion length, coronary stenosis, and FFR in these 163 lesions.
Results:
Regression analysis revealed an inverse correlation between the percentage of diameter stenosis (%DS) and FFR in group S (r = −0.83, P < 0.0001). In group I, no significant correlation was found between %DS and FFR (r = −0.06, P = 0.55), whereas lesion length was significantly inversely correlated with FFR (r = −0.79, P < 0.0001). Receiver operating characteristic curve analysis demonstrated that the best cutoff value for predicting an FFR value <0.80 was a lesion length >16.1 mm in group I (sensitivity, 86%; specificity, 94%).
Conclusions:
These study findings suggest that lesion length has a physiologically significant impact on intermediate‐grade coronary lesions. Clin. Cardiol. 2011 DOI: 10.1002/clc.22076
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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.
Recently, an aortic valve area (AVA) index (AVAI) <0.6 cm2 /m2 was proposed as an indicator of severe aortic stenosis. The purpose of the present study was to clarify the prognostic value of the ...AVAI. We identified 103 consecutive asymptomatic patients (mean age 72 ± 11 years) with severe aortic stenosis, defined by an AVA of <1.0 cm2 , who had not undergone aortic valve replacement on initial evaluation. During follow-up (median 36 ± 27 months), 31 aortic valve replacements and 20 cardiac deaths occurred. Multivariate analysis revealed that an AVAI <0.6 cm2 /m2 (hazard ratio 2.6, 95% confidence interval 1.1 to 6.3; p = 0.03) and peak aortic jet velocity (Vp) >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were associated with cardiac events but that an AVA <0.75 cm2 was not. The event-free survival of patients with an AVAI of ≥0.6 cm2 /m2 was better than that for those with an AVAI <0.6 cm2 /m2 (86% vs 41% at 3 years, p <0.01). Furthermore, patients with an AVAI of ≥0.6 cm2 /m2 and Vp of ≤4.0 m/s showed an excellent prognosis, but those without these findings had poorer outcomes. In conclusion, AVAI is a powerful predictor of adverse events in asymptomatic patients with severe aortic stenosis. Furthermore, the combination of AVAI and Vp provides additional prognostic information. Watchful observations are required for timely aortic valve replacement in patients with an AVAI of <0.6 cm2 /m2 or a Vp >4.0 m/s.
Aims
Oxidative stress plays an important role in the development and progression of heart failure (HF). Although exercise and oxidative stress are closely related, the effect of acute exercise on ...reactive oxygen species production and the fluctuation on prognosis are unclear.
Methods and results
We enrolled 94 patients who were hospitalized for worsening HF (mean age 68.0 ± 14.5 years old, 63.8% male). The changes in diacron‐reactive oxygen metabolites (d‐ROM) values, a marker of oxidative stress, before and after a cardiopulmonary exercise test were considered as Δd‐ROM. The mean follow‐up period was 24 ± 13 months, during which 15 patients had all‐cause death or left ventricular assist system implantation. Kaplan–Meier analysis demonstrated that all‐cause death or left ventricular assist system implantation was significantly higher in the Δd‐ROM‐positive group than in the Δd‐ROM‐negative group (log‐rank P = 0.047). Elevated Δd‐ROM levels were associated with increased mortality risk. Multivariate analysis adjusted for body mass index and peak oxygen uptake revealed that Δd‐ROM was an independent prognostic factor of adverse events (Tertile 3 vs. 1; hazard ratio: 4.57; 95% confidence interval: 1.21–29.77; P = 0.022).
Conclusions
Patients with HF who underwent a cardiopulmonary exercise test and had an increased oxidative stress marker level had a poor prognosis. The appropriate exercise intensity could be determined by evaluating the changes in oxidative stress status in response to acute exercise in patients with HF.
The prognostic value of T-wave alternans (TWA) during the night time in patients with Brugada syndrome (Br-S) remains unknown. We assessed TWA for risk stratification using 24-h multichannel Holter ...electrocardiogram (24-M-ECG) in Br-S. We enrolled 129 patients with Br-S grouped according to histories of ventricular fibrillation (VF),
n
= 16; syncope,
n
= 10; or no symptoms (asymptomatic),
n
= 103 and 11 controls. Precordial electrodes were attached to the third (3L-V1, 3L-V2) and fourth (4L-V1, 4L-V2 and 4L-V5) intercostal spaces. We measured the values of maximum TWA (max-TWA) during the night time (12 a.m.–6 a.m.) and the day time (12 p.m.–6 p.m.) and calculated parameters of heart rate variability. Compared to the asymptomatic and control groups, the VF and syncope groups showed significantly greater 3L-V2 max-TWA during the night time. The cutoff value for the 3L-V2 max-TWA during the night time was determined as 20 µV (sensitivity 94 % and specificity 48 %;
p
= 0.01). Multivariate analysis revealed that 3L-V2 max-TWA during the night time ≥20 µV and previous VF episodes were independent predictors of future VF episodes. During a mean follow-up period of 68 ± 37 months, 16 patients experienced VF episodes. The incidence of VF episodes was the highest during the night time (
p
< 0.001). The 3L-V2 max-TWA during the night time may be a useful predictor for VF episodes in patients with Br-S.
Several trials demonstrated that a long detection interval and a high-rate cutoff reduced implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. However, only a few data ...are available for secondary prevention (SP) patients. The aim of this study was to evaluate whether these ICD programming would be effective in reducing ICD therapies in SP patients. We enrolled 65 SP patients under ICD or cardiac resynchronization therapy with the defibrillator programmed with the same setting (conventional setting). During follow-up, we changed detection rates in each zone; cycle length (CL) ≤400 to ≤370 ms for ventricular tachycardia (VT) zone, CL ≤350 to ≤320 ms for fast VT zone, CL ≤300 to ≤270 ms for ventricular fibrillation (VF) zone, and number of intervals to detect ventricular tachyarrhythmia in VF zone: 12–24. We retrospectively compared the incidences of ICD therapies, syncope, and hospitalization due to slow VT under the detection rate between both settings. Median follow-up periods were 5.0 (interquartile range 2.5–7.8) and 2.5 years (interquartile range 2.3–2.7) in conventional and strategic settings, respectively. The incidence of appropriate ATP and shock significantly decreased in strategic setting (conventional and strategic settings: 21.2 and 4.8 ATPs per year, respectively, OR 0.18, 95 % CI 0.06–0.54,
p
= 0.002, 26.1 and 7.8 shocks per year, respectively, OR 0.29, 95 % CI 0.09–0.88,
p
= 0.03). The incidence of overall inappropriate therapy significantly decreased (conventional and strategic settings: 17.6 and 2.8 therapies per year, respectively, OR 0.14, 95 % CI 0.05–0.44,
p
= 0.01). The incidence of syncope and slow VT was not significantly different between both settings. In conclusion, ICD programming-combined long detection interval with high-rate cutoff was effective in reducing appropriate shock and inappropriate therapy without increasing the incidence of syncope and slow VT in SP patients.
Tolvaptan, a non-peptide V2-receptor antagonist, is a newly developed diuretic agent. Recently, we reported that tolvaptan has diuretic as well as anti-inflammatory and anti-fibrotic actions in ...chronic heart failure. In this study, we investigated whether tolvaptan has a cardioprotective effect in acute heart failure after myocardial infarction (MI). After MI induction, rats were randomized into 6 groups as follows: vehicle group, group treated with 15 mg∙kg−1∙day−1 furosemide, 2 groups treated with 3 or 10 mg∙kg−1∙day−1 tolvaptan, and 2 groups treated with 15 mg∙kg−1∙day−1 furosemide combined with 3 or 10 mg∙kg−1∙day−1 tolvaptan. Each agent was administered for 2 weeks, and blood pressure levels and infarct sizes were similar in all MI groups. Lower left ventricular end-systolic volumes and greater improvement of left ventricular ejection fraction were observed in the tolvaptan-treated groups compared with the vehicle group. In contrast, furosemide alone did not improve them. Sirius red staining revealed that tolvaptan significantly repressed MI-induced interstitial fibrosis in the left ventricle. MI-induced mRNA expressions related to cardiac load, inflammation, and fibrosis were significantly attenuated in the combination group. The combination treatment also repressed MI-induced mineralocorticoid receptor expression. Tolvaptan, or combination of furosemide and tolvaptan, may improve cardiac function in acute MI.
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