Inspiratory resistive breathing induces MMP-9 and MMP-12 expression in the lung.

Inspiratory resistive breathing (IRB) is characterized by large negative intrathoracic pressures and was shown to induce pulmonary inflammation in previously healthy rats. Matrix metalloproteinases (MMP)-9 and -12 are induced by inflammation and mechanical stress in the lung. We hypothesized that IRB induces MMP-9 and -12 in the lung. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve, connected to an inspiratory resistance, with the tidal inspiratory tracheal pressure set at 50% of the maximum. Quietly breathing animals served as controls. After 3 and 6 h of IRB, respiratory mechanics were measured, bronchoalveolar lavage (BAL) was performed, lung injury score was estimated, and lung MMP-9 was estimated by zymography and ELISA. MMP-9 and MMP-12 immunohistochemistry was performed. Isolated normal alveolar macrophages were incubated with BAL from rats that underwent IRB. After 18 h, MMP-9 and -12 levels were measured in supernatants, and immunocytochemistry was performed. Macrophages were treated with IL-1ß, IL-6, or TNF-α, and MMP-9 in supernatants was measured. After 6 h of IRB, leukocytes in BAL increased, and IL-1ß and IL-6 levels were elevated. Elasticity and injury score were increased after 3 and 6 h of IRB. Lung MMP-9 levels increased after 6 h of IRB. MMP-9 and MMP-12 were detected in alveolar macrophages and epithelial (bronchial/alveolar) cells after 3 and 6 h of IRB. MMP-9 and MMP-12 were found in supernatants after treatment with 6 h of IRB BAL. Cytosolic immunostaining was detected after treatment with 3 and 6 h of IRB BAL. All cytokines induced MMP-9 in culture supernatants. In conclusion, IRB induces MMP-9 and -12 in the lung of previously healthy rats.

Increased Rho kinase activity in congestive heart failure.

AIMS: Rho kinases (ROCKs) are the best characterized effectors of the small G-protein RhoA, and play a role in enhanced vasoconstriction in animal models of congestive heart failure (CHF). This study examined if ROCK activity is increased in CHF and how it is associated with the outcome in CHF. METHODS AND RESULTS: Patients admitted with CHF (n =178), disease controls (n =31), and normal subjects (n =30) were studied. Baseline ROCK activity was measured by phosphorylation of themyosin-binding subunit in peripheral leucocytes. The patients were followed up for 14.4 ± 7.2 months (range 0.5-26 months) or until the occurrence of cardiac death. The ROCK activity in CHF patients (2.93 ± 0.87) was significantly higher than that of the disease control (2.06 ± 0.38, P < 0.001) and normal control (1.57 ± 0.43, P < 0.001) groups. Similarly, protein levels of ROCK1 and ROCK2 as well as the activity of RhoA in CHF were significantly higher than in disease controls and normal controls (all P < 0.05). Dyspnoea at rest (ß =0.338, P < 0.001), low left ventricular ejection fraction (ß = -0.277, P < 0.001), and high creatinine (ß =0.202, P =0.006) were independent predictors of the baseline ROCK activity in CHF. Forty-five patients died within 2 years follow-up (25.3%). Combining ROCK activity and N-terminal pro brain natriuretic peptide (NT-proBNP) had an incremental value (log rank χ(2) =11.62) in predicting long-term mortality when compared with only NT-proBNP (log rank χ(2) =5.16, P < 0.05). CONCLUSION: ROCK activity is increased in CHF and it might be associated with the mortality in CHF. ROCK activity might be a complementary biomarker to CHF risk stratification.

Use of myeloperoxidase for risk stratification in acute heart failure.

BACKGROUND: Myeloperoxidase (MPO) is a biomarker of inflammation and oxidative stress produced by neutrophils, monocytes, and endothelial cells. Concentrations of MPO predict mortality in patients with chronic heart failure. This study sought to investigate the diagnostic accuracy and prognostic value of MPO in patients with acute heart failure (AHF). METHODS: We prospectively enrolled 667 patients presenting to the emergency department with dyspnea and observed them for 1 year. MPO and B-type natriuretic peptide (BNP) were measured at presentation. Two independent cardiologists adjudicated final discharge diagnoses. RESULTS: MPO concentrations were similar in patients with AHF (n = 377, median 139 pmol/L) and patients with noncardiac causes of dyspnea (n = 290, median 150 pmol/L, P = 0.26). The diagnostic accuracy of MPO for AHF was limited [area under the ROC curve (AUC) 0.53] and inferior to that of BNP (AUC 0.95, P < 0.001). In patients with AHF, MPO concentrations above the lowest tertile (MPO >99 pmol/L) were associated with significantly increased 1-year mortality (hazard ratio 1.58, P = 0.02). The combination of MPO (< or = 99 vs >99 pmol/L) and BNP (median of < or = 847 vs >847 ng/L) improved the prediction of 1-year mortality (hazard ratio 2.80 for both variables increased vs both low, P < 0.001). After adjustment for cardiovascular risk factors in multivariable Cox proportional hazard analysis, increases in MPO contributed significantly toward the prediction of 1-year mortality (hazard ratio 1.51, P = 0.045). CONCLUSIONS: MPO is an independent predictor of 1-year mortality in AHF, is additive to BNP, and could be helpful in identifying patients with a favorable prognosis despite increased BNP concentrations.

Ranolazine-related dyspnea on exertion.

BACKGROUND: Ranolazine is increasingly being prescribed for the treatment of chronic stable angina. This report describes an adverse effect that may be related to ranolazine. CASE SUMMARY: A 77-year-old white man with chronic renal insufficiency was evaluated for moderate dyspnea on exertion (DOE). Cardiac and pulmonary workup revealed nonobstructive coronary artery disease and mild obstructive lung disease. The patient had been taking ranolazine 500 mg daily for possible angina for the past 2 months. Given the temporal association of his symptoms with drug initiation, ranolazine was discontinued during the hospitalization. One month after discontinuing ranolazine, the patient's DOE had completely resolved; the only intervention had been discontinuation of ranolazine. The patient's Naranjo algorithm score was 3, indicating a possible adverse drug reaction. CONCLUSIONS: No previous cases of ranolazine-related DOE requiring drug cessation have been published. Ranolazine may be associated with DOE in this elderly man.

Creatine phosphokinase elevation in patients presenting to the emergency department with cocaine-related complaints.

The incidence of creatine phosphokinase (CPK) elevation was evaluated in patients presenting to an urban emergency department with any complaint related to cocaine use within the preceeding 24 hours. Patients with obvious causes of CPK elevation (ie, seizure) were excluded. Forty patients were enrolled. CPK values were elevated in 21 patients (53%). The mean CPK value for patients with an elevated CPK was 1,071 IU/L. There was no statistically significant difference between the patient's initial complaint (muculoskeletal, psychiatric, or cardiovascular) and the incidence of CPK elevation (P = .35). Thirty of the 40 patients admitted to using some other drug(s) in addition to cocaine in the preceding 24 hours. Some degree of skeletal muscle injury and CPK elevation appears to be common in patients using cocaine.

An unusual case of carnitine palmitoyl transferase deficiency.

A 36-year-old man presented with episodic exertional dyspnea, fluctuating exercise intolerance, and myoglobinuria. He never experienced cramps or myalgias. Subsequent evaluation revealed carnitine palmitoyl transferase deficiency. The unusual features of this case suggested that carnitine palmitoyl transferase deficiency may have a more diverse clinical picture than previously described.