Clinical utility of the BIWACO score for patients with atrial fibrillation after percutaneous coronary intervention.

No predictive clinical risk scores for net adverse clinical events (NACE) have been developed for patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). We evaluated NACE to develop clinically applicable risk-stratification scores in the Bleeding and thrombotic risk evaluation In patients With Atrial fibrillation under COronary intervention (BIWACO) study, a multicenter survey which has enrolled a total of 7837 patients. We also investigated the current status and time trends for the use of antithrombotic drugs. A total of 188 AF patients who had received PCI were examined. At discharge, 65% of patients were prescribed a triple therapy (TT), 6% were prescribed a dual therapy, the remaining 29% of patients received dual-antiplatelet therapy. After 4 years, the fraction of patients continuing TT decreased by 15%, whereas oral anticoagulant alone was only 2% of patients. NACE developed in 20% of patients, resulting in death in 5% of the patients, and the remaining 13% experienced bleeding events. We developed risk scores for NACE comprising the five strongest predictive items, which we designated BIWACO scores. The area under the curve was 0.774 for NACE. Our study explored the differences in treatment practices and guideline recommendations for antithrombotic therapy. We concluded that our BIWACO score is useful for predicting clinical outcomes in AF-patients after PCI.

Successful interventional revascularization utilizing hybrid procedural steps of rotational atherectomy and retrograde approach via an ipsilateral collateral.

Here, we report a case of successful interventional revascularization of the left anterior descending artery (LAD) in two heavy calcified chronic total occlusion (CTO) lesions, which were uncrossable utilizing hybrid procedural steps of local rotational atherectomy and a retrograde approach by reverse controlled antegrade and retrograde tracking (CART) technique via an ipsilateral intraseptal collateral. A-76-year-old man that had undergone previous coronary artery bypass surgery was admitted for ischemic heart failure. Coronary angiography showed that the left internal thoracic artery graft that was anastomosed to the first diagonal branch was patent. However, his native LAD had two CTOs as if the open vessel had sandwiched them. Moreover, there were no interventional collaterals. The antegrade guidewire was successfully passed through both CTOs. However, devices were uncrossable at the entry of the distal LAD-CTO. After stent deployment at the proximal CTO, local rotational atherectomy with a 1.5 mm burr was performed as plaque modification from the protruding calcified plaque at the bifurcation of the first septal branch to the distal CTO entry for the following procedure, although the dedicated guidewire was unable to pass completely through the distal CTO segment. Staged PCI to the distal LAD-CTO was performed using a retrograde approach via an ipsilateral intraseptal collateral, which had grown due to recanalization of the proximal LAD-CTO. Due to plaque modification by rotablation at the first attempt, successful interventional revascularization to the distal LAD-CTO was accomplished using the reverse CART technique.

Emerging acute unilateral pulmonary edema in a patient with pheochromocytoma.

We report a patient who presented with unilateral pulmonary edema without cardiomegaly. Our patient was finally diagnosed as having pheochromocytoma crisis.

Beneficial effect of perindopril on cardiac sympathetic nerve activity and brain natriuretic peptide in patients with chronic heart failure: comparison with enalapril.

BACKGROUND: In patients with chronic heart failure (CHF), it remains unclear whether perindopril is more cardioprotective than enalapril. METHODS AND RESULTS: Forty-five stable CHF outpatients undergoing conventional therapy including enalapril therapy were randomized to 2 groups [group I (n=24): continuous enalapril treatment; group II (n=21): enalapril was changed to perindopril]. Cardiac sympathetic nerve activity was evaluated using cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, hemodynamic parameters and neurohumoral factors before and 6 months after treatment. There was no difference in baseline characteristics between the 2 groups. In group I, there were no changes in MIBG parameters, left ventricular ejection fraction (LVEF) or plasma level of brain natriuretic peptide (BNP). In contrast, in group II the delayed heart/mediastinum count ratio was significantly increased (2.0+/-0.07 vs 2.15+/-0.07, p=0.013) and the washout rate was significantly decreased (33.0+/-1.4 vs 30.5+/-1.2, p=0.030) after 6 months compared with the baseline value. In addition, LVEF was significantly increased and the plasma BNP level was significantly decreased. CONCLUSION: These findings suggest that for the treatment of CHF, perindopril is superior to enalapril with respect of cardiac sympathetic nerve activity and BNP.

Plasma level of cardiotrophin-1 as a prognostic predictor in patients with chronic heart failure.

BACKGROUND: Cardiotrophin-1 (CT-1) is a member of the interleukin (IL-6) family of cytokines and is increased in patients with chronic heart failure (CHF). AIMS: To evaluate the prognostic role of CT-1 in patients with CHF. METHODS AND RESULTS: We measured the plasma levels of CT-1, brain natriuretic peptide (BNP), and IL-6 in 125 patients with CHF. Patients were monitored for a mean follow-up period of 2.9 years. Plasma levels of CT-1 increased with severity of CHF. There was a significant negative correlation between plasma CT-1 and left ventricular ejection fraction. There was a significant correlation between plasma CT-1 and log IL-6. During the follow-up period, 37 patients died. High plasma levels of CT-1, BNP, and IL-6 were independent predictors of mortality on stepwise multivariate analysis. The hazard ratio for mortality in patients with plasma BNP>170 pg/mL and CT-1>658 fmol/mL was 2.48 (95% confidence interval, 1.217-5.060) compared to those with plasma BNP>170 pg/mL and CT-1<658 fmol/mL (p=0.0124). CONCLUSION: These findings indicate that plasma CT-1 measurement provides additional prognostic information and that combined levels of CT-1 and BNP are more accurate at predicting mortality in patients with CHF than either marker alone.

Comparison of active renin concentration and plasma renin activity as a prognostic predictor in patients with heart failure.

BACKGROUND: Plasma renin activity (PRA) may be limited to angiotensinogen levels, which decrease in patients with heart failure (HF) because of liver congestion. METHODS AND RESULTS: To evaluate whether the plasma active renin concentration (ARC) is a more useful prognostic predictor than PRA, the plasma levels of ARC, PRA, angiotensin II, aldosterone, brain natriuretic peptide (BNP), norepinephrine, and hemodynamic parameters were measured in 214 consecutive HF patients who were already taking angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-receptor blockers (ARB). Median follow-up period was 1,197 days. Of the clinical variables, including pulmonary capillary wedge pressure, right atrial pressure, left ventricular ejection fraction, and neurohumoral factors, only high plasma levels of log ARC (p<0.0001) and log BNP (p=0.0009), but not log PRA, were significant independent prognostic predictors. Log ARC/PRA ratio was significantly higher in nonsurvivors than in survivors. Log ARC/PRA significantly correlated with pulmonary capillary wedge pressure (r=0.305, p<0.0001), right atrial pressure (r=0.222, p=0.0011), and log BNP (r=0.242, p=0.0004). CONCLUSIONS: Plasma ARC is superior to PRA and a high plasma ARC is an independent prognostic predictor in HF patients who are already receiving ACEI or ARB.

Direct comparison of transcardiac difference between brain natriuretic peptide (BNP) and N-terminal pro-BNP in patients with chronic heart failure.

BACKGROUND: Direct comparison of transcardiac increase in brain natriuretic peptide (BNP) and NT-pro-BNP has not been performed previously. AIMS: To evaluate the relation between BNP and NT-pro-BNP secretion, plasma levels and renal function. METHODS: We measured the plasma levels of BNP and NT-pro-BNP in the aortic root and coronary sinus in 326 consecutive patients with chronic heart failure (CHF). Patients were divided into two groups [group I: estimated glomerular filtration rate (eGFR)>or=60 mL/min and group II: eGFR<60 mL/min]. RESULTS: The molar level of the transcardiac increase in NT-pro-BNP is lower than that of BNP. There were no differences in haemodynamics or the transcardiac gradient of BNP and NT-pro-BNP between group I and group II. The molar ratio of the plasma NT-pro-BNP to BNP was significantly higher in group II than in group I. By stepwise multivariate analyses, not only the left ventricular (LV) ejection fraction and LV end-diastolic pressure, but also eGFR, LV mass index (LVMI) and haemoglobin were independent predictors of plasma NT-pro-BNP and BNP. CONCLUSION: The molar level of the transcardiac increase in NT-pro-BNP is lower than that of BNP; however, the influence of renal function on plasma NT-pro-BNP is greater than that on BNP.

Proteomic analysis reveals significant alternations of cardiac small heat shock protein expression in congestive heart failure.

BACKGROUND: Because congestive heart failure (CHF) is a complex syndrome with many different underlying mechanisms of worsening of heart function, it is important to recognize the global alternations in protein expression associated with the processes of CHF. METHODS AND RESULTS: The purpose of our study was to use a proteomic approach to investigate global alternations in protein expression in tachycardia induced CHF dogs. We compared the 2-dimensional electrophoresis protein patterns of left ventricular samples from the normal with those from failing myocardium. Differentially expressed cardiac proteins showed approximately 500 cardiac protein spots. A total of 20 spots (14 increased, 6 decreased) was altered in CHF, whereas the more distinguishably increased spots in CHF were identified by using mass spectrometry as alpha B crystallin, heat shock protein (HSP) 27, and HSP20, which maintain both the morphologic and functional integrity of the cardiomyocytes and increase tolerance against various types of stress. Because phosphorylation is one of the most important posttranslational modifications, we evaluated whether or not the overexpressed small HSPs were phosphorylated in CHF. Phosphoprotein staining and Western blotting demonstrated that the phosphorylation of alpha B crystallin at serine (Ser)-59 site and of HSP27 at both Ser-78 and Ser-82 sites increased in CHF. CONCLUSION: Proteomics studies can provide new insights into molecular mechanisms in CHF and phosphorylated small HSPs may be involved in preventing cardiac dysfunction.

Relationship between renal function and plasma brain natriuretic peptide in patients with heart failure.

OBJECTIVES: This study sought to evaluate the relationship between brain natriuretic peptide (BNP), renal function, and the severity of congestive heart failure (CHF). BACKGROUND: Both BNP and renal function are prognostic predictors in CHF patients. METHODS: We measured the plasma BNP level in the aortic root and coronary sinus in 366 consecutive patients with CHF. Estimated glomerular filtration rate (eGFR) by the Cockcroft-Gault equation was used as an indicator of renal function. RESULTS: By stepwise multivariate analyses, hemodynamic parameters such as left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP) but not eGFR were independent predictors of a transcardiac increase (coronary sinus-aortic root) in BNP. Regarding the plasma level of BNP in the aortic root, not only LVEF (p < 0.0001) and LVEDP (p < 0.0001) but also eGFR (p < 0.0001) were independent predictors. Patients were divided into two groups, patients with an eGFR > or =60 ml/min (group 1, n = 229) and patients with an eGFR <60 ml/min (group 2, n = 137). There was no difference in LVEF, LVEDP, or the transcardiac gradient of BNP between the two groups, but the plasma level of BNP in the aortic root was approximately two-fold greater in group 2 than in the group 1. CONCLUSIONS: These findings suggest that decreased clearance from the kidney contributes to the elevated BNP in CHF patients with renal dysfunction, especially in patients with an eGFR <60 ml/min.

Inhibition of aldosterone and endothelin-1 by carperitide was attenuated with more than 1 week of infusion in patients with congestive heart failure.

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Contribution of vascular NAD(P)H oxidase to endothelial dysfunction in heart failure and the therapeutic effects of HMG-CoA reductase inhibitor.

BACKGROUND: The vascular NAD(P)H oxidase-derived superoxide anion (O(2)-) plays a crucial role in the pathological progression of hypertension and atherosclerosis, and HMG-CoA reductase inhibitors (statins) have vascular antioxidant effects. However, it is unclear whether the vascular NAD(P)H oxidase is involved in the endothelial dysfunction of congestive heart failure (CHF) and whether HMG-CoA reductase inhibitors (statins) exert their vasoprotective effects in CHF. The present study examined both the involvement of vascular NAD(P)H oxidase in endothelial dysfunction in dogs with tachycardia-induced CHF and the therapeutic effect of a statin (pitavastatin). METHODS AND RESULTS: Femoral blood flow (FBF) responses to acetylcholine was significantly impaired in the CHF group, but were improved by pitavastatin. Vascular O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression were significantly elevated in CHF compared with the normal group. The elevated O(2)-production in the CHF group was suppressed by the NAD(P)H oxidase inhibitor, apocynin, to the normal level. In contrast, neither the gene expression nor the activity of endothelial nitric oxide synthase (eNOS) differed significantly between the normal and CHF groups. However, pitavastatin significantly suppressed O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression and increased eNOS expression and activity compared with the CHF group. CONCLUSIONS: The activated vascular NAD(P)H oxidase contributes to endothelial dysfunction in CHF, which was partly improved by pitavastatin via its inhibition of NAD(P)H oxidase.

Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway.

In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.

Transcardiac increase in tumor necrosis factor-alpha and left ventricular end-diastolic volume in patients with dilated cardiomyopathy.

BACKGROUND: It remains unclear whether tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) are secreted from the failing heart and whether there is a relationship between the transcardiac gradients of these cytokines and left ventricular (LV) remodeling. AIMS: This study evaluated the relationship between transcardiac gradients of cytokines and LV volume and function in congestive heart failure patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We measured the plasma levels of TNF-alpha and IL-6 in the aortic root (Ao) and the coronary sinus (CS) in 60 patients with DCM. There was no difference in plasma IL-6 between the Ao and the CS. However, the plasma TNF-alpha level was significantly higher in the CS than that in the Ao. There was a significant correlation between the transcardiac gradient of plasma TNF-alpha and the LV end-diastolic volume index (LVEDVI) and LV ejection fraction. According to stepwise multivariate analyses, the transcardiac increase of TNF-alpha showed an independent and significantly positive relationship with a large LVEDVI. CONCLUSIONS: These results indicate that the elevated plasma TNF-alpha is partly derived from the failing heart in patients with DCM and that TNF-alpha plays a potential role in structural LV remodeling in patients with DCM.

Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure.

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.

Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure.

BACKGROUND: Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE); however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-beta in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling METHODS AND RESULTS: We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I; 10 mg/kg twice a day; n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with the normal group; however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of tau. Chy I suppressed collagen-type I and III and transforming growth factor-beta mRNA levels and decreased fibrosis in the LV compared with the vehicle. CONCLUSIONS: The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF.

Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction.

BACKGROUND: Aldosterone (ALD) has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that ALD was extracted through the infarct heart and extracting ALD-stimulated post-infarct left ventricular (LV) remodeling. METHODS AND RESULTS: To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. However, LV ejection fraction was significantly improved in the MRA group compared with that in the non-MRA group (46.0+/-0.6% to 53.2+/-0.8% versus 46.5+/-0.8% to 51.0+/-0.8%, Pinteraction=0.012). LV end-diastolic volume index was significantly suppressed in the MRA group compared with that in non-MRA group (86.5+/-1.0 to 90.6+/-2.4 versus 87.5+/-1.3 to 106.8+/-3.5 mL/m2, Pinteraction=0.002). Transcardiac extraction of ALD through the heart was significantly suppressed in the MRA group (Pinteraction=0.001), and plasma procollagen type III aminoterminal peptide level, a biochemical marker of fibrosis, was significant lower in the MRA group compared with the non-MRA group (Pinteraction=0.002). CONCLUSIONS: These findings indicate that MRA combined with ACE inhibitor can prevent post-infarct LV remodeling better than ACE inhibitor alone in association with the suppression of a marker of collagen synthesis.

Transcardiac gradient of aldosterone before and after spironolactone in patients with congestive heart failure.

To evaluate the transcardiac extraction of aldosterone before and after spironolactone administration to patients with congestive heart failure, we measured the plasma aldosterone in the aortic root and the coronary sinus in eight congestive heart failure patients with dilated cardiomyopathy. The plasma aldosterone level was significantly lower in the coronary sinus than in the aortic root before spironolactone administration (87.5 +/- 16 versus 62.2 +/- 11 pg/ml, p = 0.01). After chronic treatment with spironolactone, there was no significant difference in the aldosterone level between the aortic root and the coronary sinus (151 +/- 49 versus 148 +/- 48 pg/ml), and the transcardiac gradient of aldosterone (aortic root to coronary sinus) was significantly decreased (25.3 +/- 7.3 versus 3.1 +/- 4.5 pg/ml, p = 0.046). These results indicate that plasma aldosterone is extracted through the heart in congestive heart failure patients with dilated cardiomyopathy, and that spironolactone inhibits the transcardiac extraction of aldosterone in congestive heart failure patients. This suggests that spironolactone blocks the effects of aldosterone on the failing heart in congestive heart failure patients with dilated cardiomyopathy.

Effects of long-acting calcium channel antagonists on neurohumoral factors: comparison of nifedipine coat-core with amlodipine.

Calcium channel antagonists can induce sympathetic hyperactivity, leading to a poor prognosis for hypertensive patients. Nifedipine formulations that allow once-daily administration are now available for use in clinical practice. To compare the effects of nifedipine with those of amlodipine, we studied 36 essential hypertensive patients. Those who had been administered nifedipine sustained-release were treated with amlodipine in place of nifedipine sustained-release, and those who had been administered amlodipine were treated with nifedipine coat-core in place of amlodipine. Substitution of nifedipine sustained-release by amlodipine had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone were significantly lower (p < 0.001-0.05) in patients taking amlodipine in place of nifedipine sustained-release. Substitution of amlodipine by nifedipine coat-core again had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone did not change significantly after the substitution. These findings indicate that, at the effective anti-hypertensive concentrations of nifedipine coat-core and amlodipine, nifedipine coat-core may not increase sympathetic nerve activity as is observed with amlodipine. The results also suggest that the duration of action of nifedipine formulations is an important determinant for nifedipine-induced hyperactivity in the reflex sympathetic nerve and the renin-angiotensin systems.