A simple and rapid method for identification of lesions at high risk for the no-reflow phenomenon immediately before elective coronary stent implantation.

We aimed to design a rapid and reliable method to identify coronary lesions at high risk for the no-reflow phenomenon before elective coronary stent implantation using integrated backscatter intravascular ultrasound (IB-IVUS). The no-reflow phenomenon occurring during elective percutaneous coronary intervention (PCI) worsens patient prognosis, regardless of whether the phenomenon is transient or persistent. We retrospectively studied 353 coronary lesions to identify factors potentially promoting the no-reflow phenomenon, including lesion location and severity. We also performed component analysis by two- and three-dimensional IB-IVUS before elective stent implantation. The cutoff values of the true lipid volume and estimated lipid volume (lipid area at the minimal lumen diameter site × total stent length) for the no-reflow phenomenon were determined by receiver operating curve analysis. Type C lesions, regardless of location and a thrombolysis in myocardial flow grade of 0, were risk factors for the no-reflow phenomenon during PCI. The estimated lipid volume was significantly correlated with the true lipid volume (R 2 = 0.778, p < 0.0001). The cutoff value of the estimated lipid volume for the no-reflow phenomenon was 132.6 mm3 (area under the curve = 0.719), and the predictive value was equivalent to that of the true lipid volume. Lesions with an estimated lipid volume of ≥132.6 mm3 had a significantly higher risk of the no-reflow phenomenon during elective stent implantation (odds ratio, 4.35; 95 % confidence interval, 1.67-12.7; p = 0.0024). The simple and rapid measurement of the estimated lipid volume immediately before stenting during PCI constitutes a reliable predictor of lesions at high risk for the no-reflow phenomenon.

Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension.

We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 +/- 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and fasudil inhalation (NO: P < 0.01, fasudil: P < 0.05), indicating that both NO and fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for fasudil but not for NO. These results suggest that inhalation of fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.

Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension.

BACKGROUND: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. METHODS AND RESULTS: Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. CONCLUSIONS: These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder.

Low forced expiratory volume in one second is associated with the history of acute coronary syndrome in patients with organic coronary stenosis.

BACKGROUND: Chronic obstructive pulmonary disease often coexists with cardiovascular diseases and airflow limitation has been known as a risk of cardiovascular death. However, the association between airflow limitation and the history of acute coronary syndrome (ACS) in patients with coronary stenosis remains to be determined. METHODS: Study subjects were 271 consecutive patients (age: 70.6±9.5 years, sex: 200 males) who underwent coronary angiography and in whom organic coronary stenosis was detected. We collected spirometric data from those patients and investigated the association of the pulmonary function and the history of ACS. We also compared the prevalence of airflow limitation of the present subjects with Japanese epidemiological data that had been previously published. RESULTS: Multivariate analysis with multiple logistic regression analysis showed that the reduced forced expiratory volume in one second (FEV1.0) less than 80% of predicted value was significantly associated with a history of ACS (odds ratio: 2.81, 95% CI: 1.27-6.20, p<0.02) independently of age, sex, body mass index, and classic coronary risk factors including smoking habit, diabetes mellitus, hypertension, and dyslipidemia. Furthermore, the airflow limitation was more prevalent in the present subjects than in the Japanese general population (25.8% vs. 10.9%, p<0.05). CONCLUSIONS: Reduced FEV1.0 is associated with a history of ACS in patients with coronary arterial stenosis irrespective of any coronary risk factors. Airflow limitation is more prevalent in patients with coronary stenosis than in the general population.

Irreversible deterioration of estimated glomerular filtration rate in patients with acute myocardial infarction after primary percutaneous coronary intervention.

Contrast-induced nephropathy is a possible complication after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (MI). Deterioration of renal function is reported to be generally reversible. However, renal insufficiency worsens the prognosis for some patients with primary PCI. We evaluated sequential changes in renal function before primary PCI and until the chronic phase. We retrospectively studied 302 patients who had undergone PCI for acute MI. Renal function was evaluated based on estimated glomerular filtration rates (eGFRs) measured at the following four points: before PCI, within 1 week after PCI, at discharge from the hospital, and 180-365 days after MI. Patients were classified into the preserved eGFR group and the reduced eGFR group according to the median eGFR change from the basal level after PCI. Changes in eGFR in the two groups had significantly different time courses. In the preserved eGFR group, eGFR values during the chronic phase did not differ from the values obtained before PCI. In contrast, eGFRs in the reduced eGFR group did not recover to pre-PCI basal levels, with the median decrease being 10.3 mL/min/1.73 m2. The eGFR change after PCI was the strongest predictor of eGFR change during the chronic phase. In the reduced eGFR group, incidence of major adverse cardiac events was significantly higher (logrank: p = 0.048), and the hazard ratio was 2.28 (95 % confidence interval 1.02-5.60). A decline in eGFR after primary PCI for acute MI is not uncommon, and it appears to remain irreversible, even during the chronic phase.

The systemic inflammation-based Glasgow Prognostic Score as a prognostic factor in patients with acute heart failure.

AIMS: By combining C-reactive protein and serum albumin concentrations, the Glasgow Prognostic Score (GPS) provides valuable predictions of prognosis in patients with cancer. Both systemic inflammatory response and malnutrition are also common in patients with heart failure. We evaluated the efficacy of the GPS for predicting the prognoses of patients with acute decompensated heart failure (ADHF). METHODS: We investigated 336 patients who were admitted with ADHF. The GPS (0, 1, and 2) was defined as follows: patients with both elevated C-reactive protein (>1.0 mg/dl) and hypoalbuminemia (<3.5 g/dl) were allocated a score of 2, patients with only one of these biochemical abnormalities were allocated a score of 1, and patients with neither of these abnormalities were allocated a score of 0. RESULTS: During the follow-up period (mean ±â€ŠSD: 504 ±â€Š471 days), 71 patients (21.1%) died. Relative to a GPS of 0, the hazard ratios for all-cause death were 3.40 (95% confidence interval 1.81-6.45) for a GPS of 2 and 1.97 (95% confidence interval 1.06-3.66) for a GPS of 1, as determined using adjusted Cox proportional-hazards analysis. CONCLUSIONS: The GPS, which is based on systemic inflammation, is useful for predicting the prognoses of hospitalized patients with ADHF.

Detection of asymptomatic cardiac metastasis and successful salvage chemotherapy comprising a prednisone, Etoposide, procarbazine, and cyclophosphamide regimen in an elderly Japanese patient suffering from a delayed recurrence of diffuse large B-cell lymphoma.

We report a case of facial diffuse large B-cell lymphoma (DLBCL) associated with recurrent metastasis in the heart and other sites in a 76-year-old Japanese woman. Initially, she developed DLBCL in her left upper eyelid that spread into the left orbit (Ann Arbor classification stage I). The lesion went into clinical regression after 4 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by radiotherapy. More than 3 years later, the lymphoma recurred in her facial skin, together with metastases in the mediastinal lymph nodes and the heart; the tumor in the heart was successfully detected by PET/CT and cardiac MRI. To treat the recurrent lesions, we performed a salvage chemotherapy regimen comprising prednisone, etoposide, procarbazine, and cyclophosphamide, which successfully induced tumor regression.

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin-angiotensin system in hypertensive rats.

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg(-1) i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg(-1) day(-1)). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-beta2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats.

Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism still remains to be fully elucidated. We have previously demonstrated the important roles of Rho-kinase pathway in the molecular mechanisms of cardiovascular fibrosis/hypertrophy and oxidative stress, but not examined in the development of heart failure. Therefore, we examined in this study whether Rho-kinase pathway is also involved in the pathogenesis of DHF in Dahl salt-sensitive rats, an established animal model of DHF. They were maintained with or without fasudil, a Rho-kinase inhibitor (30 or 100 mg/kg/day, PO) for 10 weeks. Untreated DHF group exhibited overt heart failure associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production. Fasudil treatment significantly ameliorated those DHF-related myocardial changes. Western blot analysis showed that cardiac Rho-kinase activity was significantly increased in the untreated DHF group and was dose-dependently inhibited by fasudil. Importantly, there was a significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity. These results indicate that Rho-kinase pathway plays an important role in the pathogenesis of DHF and thus could be an important therapeutic target for the disorder.

Colchicine, a microtubule depolymerizing agent, inhibits myocardial apoptosis in rats.

Heart failure is the most common cardiovascular disease with high mortality and morbidity. Both enhanced microtubule polymerization and cardiomyocyte apoptosis are involved in the pathogenesis of heart failure. However, the link between the two mechanisms remains to be elucidated. In this study, we thus address this important issue in cultured cardiomyocytes from Wistar rats in vitro and in angiotensin II (ATII)-infused rats in vivo. Confocal microscopy examination showed that in cultured rat cardiomyocytes, micrographic density of microtubules was increased by paclitaxel, a microtubule-polymerizing agent, and decreased by colchicine, a microtubule-depolymerizing agent, but not affected by ATII, isoproterenol, or tumor necrosis factor-alpha alone. Immunoblotting analysis showed that Bax/Bcl-2 ratio, which is associated with the activation of caspase-3, was significantly increased in ATII-stimulated cultured cardiomyocytes in vitro and in ATII-infused rats in vivo, both of which were inhibited by co-treatment with colchicine. Caspase-3 and TUNEL assay to detect apoptosis in vitro demonstrated that paclitaxel or ATII alone significantly enhanced and their combination further accelerated cardiomyocyte apoptosis, which was again significantly inhibited by colchicine. Caspase-3 and TUNEL assay in vivo also demonstrated that ATII infusion significantly increased myocardial apoptosis and that co-treatment with colchicine significantly suppressed the apoptosis. In conclusion, these results indicate that a microtubule-depolymerizing agent could be a potential therapeutic strategy for treatment of heart failure.

Portopulmonary hypertension: hemodynamics, pulmonary angiography, and configuration of the heart.

BACKGROUND: The goal of the present study was to examine the cardiac configuration and pulmonary vascular changes in patients with portopulmonary hypertension (PPHTN) and compare them with those of idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: The subjects were 10 patients with PPHTN and 18 with IPAH. In PPHTN, the increases in the right ventricular end-diastolic volume index (89+/-19 vs 128+/-50 ml/m2; p=0.04), right end-systolic volume index (50+/-19 vs 95+/-47 ml/m 2; p=0.02) and right ventricular mass index (47+/-18 g/m2 vs 79+/-31; p=0.04) were low compared with IPAH. The decrease in the right ventricular ejection fraction was also low in PPHTN (45+/-10 vs 28+/-13%; p=0.01). The degree of sparse arborization and abrupt narrowing on wedged pulmonary angiography was moderate in PPHTN compared with IPAH. In PPHTN, the proximal pulmonary arteries were dilated near the segmental arteries, which were narrow in IPAH. CONCLUSION: Changes in the configuration of the heart were moderate in PPHTN compared with those in IPAH. The degree of sparse arborization and abrupt narrowing were also moderate in PPHTN.

Efficacy of acute inhalation of nitric oxide in patients with primary pulmonary hypertension using chronic use of continuous epoprostenol infusion.

BACKGROUND: There have only been a few reports published on combination therapy for patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Fifteen patients with PPH (4 men and 11 women, 34.5+/-12.1 years old) had received chronic administration of epoprostenol and the additive effects of inhaled nitric oxide (NO) and the hemodynamic changes were evaluated. In addition, the difference in the effect of acute NO loading before and after the epoprostenol therapy was compared in 6 of these patients. Under chronic use of epoprostenol, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance were decreased with acute inhalation of NO. However, cardiac output, mean aortic pressure and systemic vascular resistance were unchanged. As a result, the pulmonary to systemic vascular resistance ratio was reduced. Moreover, after chronic use of epoprostenol, the change (delta) in cardiac output with NO inhalation was increased and the NO-induced decrease in pulmonary vascular resistance was augmented compared to those before the induction. CONCLUSION: Nitric oxide inhalation further improved the hemodynamics when combined with chronic use of epoprostenol in PPH patients. These results suggest the possibility that combination therapies can be used in the treatment for PPH patients.