Acute kidney injury due to pulmonary embolism: the case for 'congestive renal failure'.

The development of acute kidney injury in patients with pulmonary embolism (PE) has not been well documented. We report a patient who developed acute oliguria in the setting of massive PE. Catheter embolectomy followed by ultrafiltration resulted in an immediate and dramatic improvement in urine output. Uncharacteristically, serum creatinine did not rise during the oliguric phase for several days until after embolectomy, and there were no metabolic derangements. Our observation that embolectomy and ultrafiltration helped with hemodynamics and renal perfusion despite decreased cardiac output suggests that right ventricular failure from both pressure and volume overload may have been central to this process. We review the older and recent literature in support of our observations.

Determinants of right ventricular failure in patients admitted with acute left heart failure.

Pulmonary hypertension, which may lead to right ventricular (RV) failure, increases with left ventricular (LV) diastolic dysfunction severity. The prevalence and determinants of RV failure were analyzed in 120 patients admitted with acute left heart (LH) failure. Patients were divided into RV failure (n=50) and non-RV failure (n=70) groups. The prevalence of RV failure was found to be 42%. In both groups, two thirds of the patients had isolated LV diastolic dysfunction and the rest had combined LV systolic and diastolic dysfunction. Patients in the RV failure group were characterized by higher LV diastolic grade (2.2 ± 0.6 vs 1.84 ± 0.7; P=.0070), pulmonary artery systolic pressure (PASP; 57.8 ± 15.3 vs 50.14 ± 12.1 mm Hg; P=.0028), right atrial enlargement (92% vs 25.7%; P=.000001), and more-than-moderate tricuspid regurgitation (58% vs 27.1%; P=.0006). RV failure is a frequent finding in patients with advanced LH failure. It is strongly associated with the severity of LV diastolic dysfunction and the severity of PASP.

Differentiating pulmonary arterial and pulmonary venous hypertension and the implications for therapy.

Pulmonary arterial and pulmonary venous hypertension develop from distinctly different etiologies. Pulmonary arterial hypertension (PAH), or Group 1 pulmonary hypertension (PH), is a precapillary PH that arises idiopathically or as the result of a divergent array of causes, including connective tissue disease. Pulmonary venous hypertension (PVH), or Group 2 PH, primarily manifests as a postcapillary PH in the setting of left heart failure or valvular disease. A subset of PVH patients, however, develop a reactive precapillary component of PH that mimics PAH. These patients can be misdiagnosed as having Group 1 PH by 2-dimensional echocardiography and are sometimes treated as such, which leads to exacerbation of heart failure. Therefore, 2-dimensional or Doppler echocardiography alone cannot be used to differentiate between these two classifications of PH. This highlights the need for right heart catheterization in the clinical assessment and diagnostic work-up of PH. The combination of imaging and invasive hemodynamic assessment by right heart catheterization provides the best diagnostic approach to ensure proper delineation of pulmonary arterial and pulmonary venous hypertension, and in turn leads to appropriate treatment.

A case of acute cardiomyopathy and pericarditis associated with methylphenidate.

Methylphenidate is a potent central nervous system stimulant that exerts its effects by increasing synaptic levels of dopamine and norepinephrine. It has become key to treating attention deficit-hyperactivity disorder (ADHD) in children and adolescents. As the use of stimulant medications has ballooned in the past decade, so too has awareness of the cardiovascular complications of these drugs. Effects on heart rate and blood pressure as well as tachyarrhythmias have been well described. However, acute cardiomyopathy and pericarditis secondary to methylphenidate use has been rarely reported. We report the case of a 17-year-old male who developed chest pain, elevated cardiac biomarkers, and acute left ventricular dysfunction following a single dose of methylphenidate. The risk of cardiomyopathy in the setting of methylphenidate treatment should prompt further study on the safety of this drug, and lead to ways of identifying those at risk of developing these complications.

Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells.

The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in tumorigenesis. Frequent promoter hypermethylation of SFRPs has been identified in human cancer. Restoration of SFRP function attenuates Wnt signaling and induces apoptosis in a variety of cancer types. Wnt signaling is known to inhibit apoptosis through activation of beta-catenin/Tcf-mediated transcription. Recently, we identified aberrant Wnt activation as a result of Dishevelled overexpression in malignant mesothelioma. Here, we report that silencing of SFRP4 is correlated with promoter hypermethylation in beta-catenin-deficient mesothelioma cell lines. Reexpression of SFRP4 in these beta-catenin-deficient mesothelioma cell lines blocks Wnt signaling, induces apoptosis, and suppresses growth. Conversely, knocking down SFRP4 by small interfering RNA in cell lines expressing both SFRP4 and beta-catenin stimulates Wnt signaling, promotes cell growth, and inhibits chemodrug-induced apoptosis. Our results suggest that methylation silencing of SFRP4 may play an important role in aberrant Wnt activation in mesothelioma even in the absence of beta-catenin. Our data also suggest that beta-catenin-independent noncanonical pathway(s) may be involved in the apoptotic inhibition caused by activation of Wnt signaling.

Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma.

Secreted frizzled-related proteins (sFRPs) comprise a family of five secreted glycoproteins that antagonize Wnt signaling. Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Thus, role of sFRP as a negative regulator of Wnt signaling may have important implications in tumorigenesis, and its downregulation has been correlated with human cancers. Recently, we reported Wnt signaling and dishevelled (Dvl) overexpression in malignant pleural mesothelioma (MM). Here, we report significant transcriptional downregulation of the SFRP gene family in MM primary tissues and cell lines as well as several other cancer cell lines (breast, lung, glioma, and cervical) compared to normal cells. One or more SFRPs were downregulated in approximately 85% (18 of 21) of primary MM tumor specimens compared to normal pleural tissue. Eight of the nine cancer cell lines we examined showed silencing of the SFRP family. Methylation-specific PCR (MSP) analysis showed that SFRP1, SFRP4, and SFRP5 gene promoters are frequently methylated in MM primary tissue (>80%). Furthermore, transfection of the SFRP gene construct into MM cell lines lacking SFRP expression resulted in apoptosis and growth suppression. Our results suggest that methylation silencing of SFRPs may be one of the important mechanisms of aberrant Wnt signaling activation in MM.