Correlation of pulmonary capillary wedge pressure with left atrial pressure in patients with mitral stenosis undergoing balloon valvotomy.

AIMS: We sought to evaluate the correlation between PCWP and LAP and to compare transmitral gradients obtained with LAP and PCWP in MS, before and after balloon mitral valvotomy (BMV). METHODS: Consecutive patients with MS for BMV were included in this prospective cohort study. Simultaneous PCWP and LAP were recorded followed by simultaneous left atrium-left ventricular (LA-LV) and pulmonary capillary wedge pressure-left ventricular (PCWP-LV) gradients before and after BMV. RESULTS: There were 30 patients with a mean age of 41 yrs (males 10 (33.3%), females 20 (66.7%)). There was no significant difference between mean LAP and mean PCWP before BMV (21.3mmHg and 22.3mmHg, respectively) or after BMV (15.3mmHg and 17.3mmHg, respectively). There was excellent correlation between mean PCWP and mean LAP before BMV (r=0.95) (p<0.001) and after BMV (r=0.85) (p<0.001). The phasic components of the pressures (a and v waves) of LAP and PCWP also showed good correlation before and after BMV. Further, transmitral gradients assessed by LA-LV and PCWP-LV pressures showed excellent correlation before BMV (r=0.95) (p<0.001) and after BMV (r=0.95) (p<0.001). CONCLUSION: In patients with MS undergoing balloon valvotomy, PCWP shows good correlation with LAP. Transmitral gradients obtained with PCWP and LAP also correlate well after correction of phase lag in PCWP tracing. Hence, PCWP can be used for reliable measurement of transmitral gradient.

Prognostic significance of coronary sinus filling time in patients with angina and normal coronaries at one year follow up.

BACKGROUND: Coronary sinus filling time (CSFT) has been proposed as a simple method for assessment of coronary microvascular function in patients with angina and normal coronaries. But its correlation with inducible ischemia and prognostic significance in predicting future cardiovascular events has not been studied. The present study assessed the prognostic significance of CSFT during one year of follow up. METHODS: We compared coronary sinus filling time of patients with angina and normal coronaries with that of control population. Control group was formed by those patients with supraventricular arrhythmia undergoing radiofrequency ablation and having normal coronaries. Baseline treadmill test (TMT) parameters like workload, duration and Duke Score were assessed. Patients were followed up for one year and a composite of cardiovascular mortality and non-fatal myocardial infarction was analyzed. Number of patients presenting to emergency or outpatient department with recurrent chest pain symptoms during one year follow up was considered for secondary outcome analysis. Coronary sinus filling time was analyzed with respect to cardiovascular events, repeat hospitalization for recurrent angina and TMT parameters. RESULTS: Total 72 patients and 16 controls were studied. Mean CSFT value in the study group was 5.31 ± 1.03 sec and in the control group was 4.16 ± 0.72 sec and the difference was significant (p value = 0.0001). No correlation was found between baseline and repeat TMT parameters with CSFT. There was no cardiovascular mortality or hospitalization for non-fatal MI during one year follow up. But patients with frequent emergency or outpatient department visits with chest pain had a high CSFT compared with asymptomatic patients (p value = 0.005). CONCLUSION: Coronary sinus filling time may be used as a simple marker of microvascular dysfunction in patients with angina and normal coronaries. Patients with recurrent chest pain symptoms after one year follow up were found to have high CSFT compared to asymptomatic patients.

Cystic lymphangioma of pericardium presenting as isolated chylopericardium - a case report.

Isolated chylopericardium due to cystic lymphangioma of pericardium is a rare entity. We report a case of asymptomatic chylopericardium in a young male who presented with cardiomegaly. Echocardiography revealed massive pericardial effusion without tamponade. Pericardiocentesis yielded 1.25 L of tea-colored fluid which showed triglyceride level of 1723 mg/dL and cholesterol of 1021 mg/dL with a cholesterol to triglyceride ratio of <1, characteristic of chylous fluid. Lymphoscintigraphy using 99Tc demonstrated lymphatic leak around the heart region. Fusion of MRI images with lymphoscintigraphy was taken with a view of localizing the leak site; it demonstrated enhancement in the pericardial space. Surgery was done via right lateral thoracotomy. Thoracic duct was ligated above diaphragm and pericardial window created by anterior pericardiectomy. The patient had an uneventful recovery and was well after 6 months of follow up. Pericardial biopsy showed cystic lymphangioma of pericardium.

Isolated pulmonary valve endocarditis: A case report and review of literature.

Isolated pulmonic valve endocarditis is an uncommon clinical entity and is usually associated with intravenous drug abuse. We describe a case of isolated pulmonary valve endocarditis in a young woman with no apparent precipitating factors other than a history of recent normal delivery. During the clinical course she suffered a pulmonary embolism which could be managed conservatively and she was discharged after a 4-week course of antibiotic therapy. The literature on the isolated pulmonary valve endocarditis is reviewed. .

Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases.

Protein kinases c-Abl, b-Raf, and p38alpha are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38alpha inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets. Although the discovery of this class of kinase inhibitors has increased the level of emphasis on the design of DFG-out inhibitors, the structural determinants for their binding and stabilization of the DFG-out conformation remain unclear. To improve our understanding of these determinants, we determined cocrystal structures of Imatinib and Sorafenib with p38alpha. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38alpha in comparison with BIRB-796, including binding kinetics, binding interactions, the solvent accessible surface area (SASA) of the ligands, and stabilization of key structural elements of the protein upon ligand binding. Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases.

Mutagenesis of p38alpha MAP kinase establishes key roles of Phe169 in function and structural dynamics and reveals a novel DFG-OUT state.

In order to study the role of Phe169 in p38alpha MAP kinase structure and function, wild-type p38alpha and five p38alpha DFG motif mutants were examined in vitro for phosphorylation by MKK6, kinase activity toward ATF2 substrate, thermal stability, and X-ray crystal structure. All six p38alpha variants were efficiently phosphorylated by MKK6. However, only one activated p38alpha mutant (F169Y) possessed measurable kinase activity (1% compared to wild-type). The loss of kinase activity among the DFG mutants may result from an inability to correctly position Asp168 in the activated form of p38alpha. Two mutations significantly increased the thermal stability of p38alpha (F169A DeltaTm = 1.3 degrees C and D168G DeltaTm = 3.8 degrees C), and two mutations significantly decreased the stability of p38alpha (F169R DeltaTm = -3.2 degrees C and F169G DeltaTm = -4.7 degrees C). Interestingly, X-ray crystal structures of two thermally destabilized p38alpha-F169R and p38alpha-F169G mutants revealed a DFG-OUT conformation in the absence of an inhibitor molecule. This DFG-OUT conformation, termed alpha-DFG-OUT, is different from the ones previously identified in p38alpha crystal structures with bound inhibitors and postulated from high-temperature molecular dynamics simulations. Taken together, these results indicate that Phe169 is optimized for p38alpha functional activity and structural dynamics, rather than for structural stability. The alpha-DFG-OUT conformation observed for p38alpha-F169R and p38alpha-F169G may represent a naturally occurring intermediate state of p38alpha that provides access for binding of allosteric inhibitors. A model of the local forces driving the DFG IN-OUT transition in p38alpha is proposed.