Role of endothelial nitric oxide synthase and collagen metabolism in right ventricular remodeling due to pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated. METHODS AND RESULTS: RV autopsy samples from 6 PH patients with RV failure against 3 age- and sex-matched controls were first examined. Next, RV remodeling in 2 mouse models of chronic hypoxia-induced PH with endothelial nitric oxide synthase-deficient (eNOS(-/-)) and collagenase-resistant knock-in (Col(R/R)) mice were examined. In humans, RV failure was associated with RV hypertrophy, interstitial and perivascular fibrosis, decreased RV capillary density and increased macrophage recruitment. Furthermore, immunostaining showed that perivascular matrix metalloproteinase-2 was increased in PH patients with RV failure. In animals, both hypoxic eNOS(-/-) and Col(R/R) mice developed a greater extent of RV hypertrophy, perivascular remodeling and macrophage infiltration compared with wild-type mice. Capillary rarefaction was developed in hypoxic eNOS(-/-) mice, while Col(R/R) mice were able to increase their capillary density in the RV in response to chronic hypoxia. Both mouse models showed increased autophagy even under normoxic condition. CONCLUSIONS: These results indicate that RV remodeling occurs early during PH development through fibrosis, perivascular remodeling, capillary rarefaction and autophagy, in which the eNOS pathway and collagen metabolism might be involved.

Combination therapy with fasudil and sildenafil ameliorates monocrotaline-induced pulmonary hypertension and survival in rats.

BACKGROUND: Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary artery (PA) remodeling, elevated PA pressure and right ventricular (RV) failure. It has been previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, whether combination therapy with fasudil and sildenafil further ameliorates PH in rats was examined. METHODS AND RESULTS: PH was induced in Sprague-Dawley rats by the use of a single subcutaneous monocrotaline (MCT) injection, which caused PA remodeling, elevated RV systolic pressure (RVSP), and RV hypertrophy (RVH). While fasudil and sildenafil monotherapy inhibited the development of MCT-induced PH in the prevention and treatment protocols, their combination therapy further improved RVSP and RVH. Moreover, a histological examination demonstrated significant improvements of PA remodeling in the combination group compared with the monotherapy groups. An echocardiographic examination also revealed significant reduction in RV diameter in the combination group compared with the monotherapy groups. Mechanistic experiments revealed significant inhibition of Rho-kinase activity in PA trunk, lung and RV tissues in the combination group as well as in the monotherapy groups. Finally, the combination therapy markedly improved the long-term survival compared with the monotherapy groups. CONCLUSIONS: These results indicate that the combination therapy with fasudil and sildenafil shows the synergistic effects through the inhibition of Rho-kinase activity for the treatment of PH.

Rho-kinase activation in patients with heart failure.

BACKGROUND: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. METHODS AND RESULTS: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19 ± 0.06 vs. 0.97 ± 0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14 ± 0.02 vs. 0.77 ± 0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. CONCLUSIONS: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.

An empirical assessment of boarding and quality of care: delays in care among chest pain, pneumonia, and cellulitis patients.

BACKGROUND: As hospital crowding has increased, more patients have ended up boarding in the emergency department (ED) awaiting their inpatient beds. To the best of our knowledge, no study has compared the quality of care of boarded and nonboarded patients. OBJECTIVES: This study sought to examine whether being a boarded patient and boarding longer were associated with more delays, medication errors, and adverse events among ED patients admitted with chest pain, pneumonia, or cellulitis. METHODS: This study was a retrospective cohort design in which data collection was accomplished via medical record review from two urban teaching hospitals. Patients admitted with chest pain, pneumonia, or cellulitis between August 2004 and January 2005 were eligible for inclusion. Our outcomes measures were: 1) delays in administration of home medications, cardiac enzyme tests, partial thromboplastin time (PTT), and antibiotics; 2) medication errors; and 3) adverse events or near misses. Primary independent variables were boarded status, boarding time, and boarded time interval. Multiple logistic regression models controlling for patient, ED, and hospital characteristics were used. RESULTS: A total of 1,431 patient charts were included: 811 with chest pain, 387 with pneumonia, and 233 with cellulitis. Boarding time was associated with an increased odds of home medication delays (adjusted odds ratio [AOR] = 1.07, 95% confidence interval [CI] = 1.05 to 1.10), as were boarded time intervals of 12, 18, and 24 hours. Boarding time also was associated with lower odds of having a late cardiac enzyme test (AOR = 0.93, 95% CI = 0.88 to 0.97). CONCLUSIONS: Boarding was associated with home medication delays, but fewer cardiac enzyme test delays. Boarding was not associated with delayed PTT checks, antibiotic administration, medication errors, or adverse events/near misses. These findings likely reflect the inherent resources of the ED and the inpatient units.