Protein kinase C-alpha regulation of gallbladder Na+ transport becomes progressively more dysfunctional during gallstone formation.

Gallbladder Na+ absorption and biliary Ca2+ are both increased during gallstone formation and may promote cholesterol nucleation. Na+/H+ exchange (NHE) is a major pathway for gallbladder Na+ transport. Ca2+-dependent second messengers, including protein kinase C (PKC), inhibit basal gallbladder Na+ transport. Multiple PKC isoforms with species- and tissue-specific expression have been reported. In this study we sought to characterize Ca2+-dependent PKC isoforms in gallbladder and to examine their roles in Na+ transport during gallstone formation. Gallbladders were harvested from prairie dogs fed either nonlithogenic chow or 1.2% cholesterol-enriched diet for varying periods to induce various stages of gallstone formation. PKC was activated with the use of phorboldibutyrate, and we assessed gallbladder NHE regulation by measuring unidirectional Na+ flux and dimethylamiloride-inhibitable 22Na+ uptake. We measured gallbladder PKC activity with the use of histone III-S phosphorylation and used Gö 6976 to determine PKC-alpha contributions. Gallbladder PKC isoform messenger RNA and protein expression were examined with the use of Northern- and Western-blot analysis, respectively. Prairie dog and human gallbladder expresses PKC-alpha, betaII, and delta isoforms. The PKC activation significantly decreased gallbladder J(Na)(ms) and reduced baseline 22Na+ uptake by inhibiting NHE. PKC-alpha mediated roughly 42% of total PKC activity under basal conditions. PKC-alpha regulates basal gallbladder Na+ transport by way of stimulation of NHE isoform NHE-2 and inhibition of isoform NHE-3. PKC-alpha blockade reversed PKC-induced inhibition of J(Na)(ms) and 22Na+ uptake by about 45% in controls but was progressively less effective during gallstone formation. PKC-alpha contribution to total PKC activity is progressively reduced, whereas expression of PKC-alpha mRNA, and protein increases significantly during gallstone formation. We conclude that PKC-alpha regulation of gallbladder NHE becomes progressively more dysfunctional and may in part account for the increased Na+ absorption observed during gallstone formation.

Physiologic and hemodynamic basis of ventricular assist devices.

Heart failure is a particularly complex disorder with etiology that is primary in nature or secondary to other systemic diseases, including hypertension, diabetes, and atherosclerosis. The pathogenesis appears to result, in part, from extensive abnormal interactions among tissues, such as the heart, vasculature, kidney, lungs, and sympathetic nervous system. Improvements in understanding this complex disorder, particularly factors that contribute to cardiac cell cycle alterations, gene activation and re-expression resulting in cardiac remodeling and, eventually, maladaption are paramount. Clinical experience with the current generation of mechanical blood pumps continues to be promising; nonetheless, these devices are not the definitive therapy for all patients with heart failure. The next generation of devices capable of mimicking many of the native heart pump attributes, such as responsiveness to preload, afterload, contractility, and beat rate, will broaden the use of this technology. In addition to solving the fundamental engineering challenges (size, energy supply, biocompatibility, durability, and portability), implantable heart pumps that are physiologically adaptive would enhance the treatment strategies for prolonged chronic support. The ultimate measure of device mediated success is to show improvements that extend beyond a favorable hemodynamic profile and include nutritional status and metabolic and neurohormonal levels and must demonstrate improved exercise tolerance and a better quality of life.

Improved survival with ventricular assist device support in cardiogenic shock after myocardial infarction.

BACKGROUND: Cardiogenic shock after acute myocardial infarction is associated with a very high mortality rate. METHODS: A retrospective review was performed of records of all patients supported with an Abiomed device at our institution between 1994 and 2002 to identify those patients who underwent device insertion for the treatment of acute myocardial infarction complicated by cardiogenic shock (AMI-CS). RESULTS: Seventeen patients who were suffering from AMI-CS and for whom medical management was failing were supported using the Abiomed BVS 5000. The average age of these patients was 57.6 years. Eleven patients were suffering primarily from left ventricular dysfunction and were supported with a left ventricular assist device (LVAD). Eight of these patients were weaned from device support, a nd 6 survived to hospital discharge (54%). In contrast, 6 patients presented with biventricular failure and were supported with biventricular VADs (BiVADs). None of these BiVAD patients could be weaned from device support. Two BiVAD patients underwent cardiac transplantation, and only one survived. CONCLUSION: In the presence of left ventricular failure producing cardiogenic shock after myocardial infarction, LVAD support can produce a 54% survival rate in those patients w ho are failing medical management. However, in patients in biventricular failure after myocardial infarction, BiVAD support may be used to stabilize the patient until transplantation, but the overall prognosis remains poor.