Angelo A. Vlessis

Infective Endocarditis: Ten-Year Review of Medical and Surgical Therapy

BACKGROUND Infective endocarditis is a complex disease process. Optimal outcome often requires both medical and surgical expertise. The need for and timing of surgical intervention is controversial and continues to evolve in parallel to advancements in diagnosis and treatment. Our experience with the treatment of infective endocarditis is reviewed herein. METHODS A retrospective review was compiled of 140 consecutive patients who fulfilled the modified von Reyn criteria for the diagnosis of endocarditis between January 1982 and April 1992. RESULTS Patient characteristics, symptoms, and risk factors are described. Follow-up averaged 3.5 +/- 0.8 years and totaled 491 patient-years. New York Heart Association functional class at presentation had a significant influence on survival (p < 0.0001). Long-term survival was significantly greater (p = 0.036) in patients treated medically/surgically than those treated with medical therapy alone (75% versus 54% at 5 years). Medical treatment of aortic and prosthetic endocarditis was associated with higher mortality (58% and 67%, respectively) when compared with combined medical/surgical treatment (28% and 38%, respectively). Among the survivors, New York Heart Association class at follow-up was better (p < 0.0001) in the medical/surgical group (1.05 +/- 0.04) versus the medical treatment group (1.70 +/- 0.14). CONCLUSIONS Combined medical/surgical treatment for infective endocarditis is associated with improved survival. Patients with aortic or prosthetic endocarditis are identified as subgroups that benefit most from surgical intervention. Valvular dysfunction incited by the infective process is an important factor that should be weighed carefully in the therapeutic decision.

Mechanism of peroxide-induced cellular injury in cultured adult cardiac myocytes.

Reactive oxygen species contribute to the tissue injury seen after reperfusion of ischemic myocardium. We propose that toxicity originates from the effect that mitochondrial peroxide metabolism has on substrate entry into oxidative pathways. To support our contention, cultured adult rat cardiomyocytes were incubated with physiological concentrations of peroxide. The cellular extract and incubation medium were analyzed for adenine nucleotides and purines by reverse‐phase high‐pressure liquid chromatography. Cellular glutathione efflux was determined by enzymatic analysis of the incubation medium. Pyruvate dehydrogenase (PDH) activity was determined in the cultured myocytes as well as in freshly isolated cardiac mitochondria using [1‐C14]pyruvate. Extracellular glutathione rose 3.3‐fold in response to small doses of peroxide (≈ 108 nmol/mg protein). Likewise, small quantities of peroxide reduced total cellular adenine nucleotides to 50–60% of control values with only a modest (0.95–0.91) reduction in energy charge ((ATP+ ½ ADP)/(ATP+ADP+AMP)). Peroxide‐treated myocytes selectively release inosine and adenosine, as only these two purine degradation products were detected in the incubation medium. The most dramatic response was a peroxide dose‐dependent inhibition of PDH activity in cultured myocytes as well as freshly isolated mitochondria; just 65 and 30 nmol peroxide/mg protein induced a 50% reduction in cellular and mitochondrial PDH activity, respectively. In conclusion, physiological quantities of peroxide potently inhibit PDH in cultured cardiomyocytes and isolated cardiac mitochondria. PDH inhibition blocks the aerobic oxidation of glucose and inhibits the oxidative phosphorylation of ADP, which in turn leads to cellular adenine nucleotide degradation.—Vlessis, A. A.; Muller, P.; Bartos, D.; Trunkey, D. Mechanism of peroxide‐induced cellular injury in cultured adult cardiac myocytes. FASEB J. 5: 2600‐2605; 1991.

Effect of peroxide, sodium, and calcium on brain mitochondrial respiration in vitro: potential role in cerebral ischemia and reperfusion.

Mitochondrial pyruvate‐supported respiration was studied in vitro under conditions known to exist following ischemia, i.e., elevated extramitochondrial Ca2+, Na+, and peroxide. Ca2+ alone (7–10 nmol/mg) decreased state 3 and increased state 4 respiration to 81 and 141% of control values, respectively. Sodium (15 mM) and/or tert‐butyl hydroperoxide (tBOOH; up to 2,000 nmol/mg protein) alone had no effect on respiration; however, Na+ or tBOOH in combination with Ca2+ dramatically altered respiration. Respiratory inhibition induced by Ca2+ and tBOOH does not involve pyruvate dehydrogenase (PDH) inhibition since PDH flux increased linearly with tBOOH concentration (R= 0.96). Calcium potentiated tBOOH‐induced mitochondrial NAD(P)H oxidation and shifted the redox state of cytochrome b from 67 to 47% reduced. Calcium (5.5 nmol/mg) plus Na+ (15 mM) decreased state 3 and increased state 4 respiratory rates to 55 and 202% of control values, respectively. Sodium‐ as well as tBOOH‐induced state 3 inhibition required mitochondrial Ca2+ uptake because ruthenium red addition before Ca2+ addition negated the effect. The increase in state 4 respiration involved Ca2+ cycling since ruthenium red immediately returned state 4 rates back to control values. The mechanisms for the observed Ca2+‐, Na+‐, and tBOOH‐induced alterations in pyruvate‐supported respiration in vitro are discussed and a multifactorial etiology for mitochondrial respiratory dysfunction following cerebral ischemia in vivo is proposed.

Importance of spontaneous α-ketoacid decarboxylation in experiments involving peroxide

The potential role of spontaneous α-ketoacid decarboxylation as a source of interference in experiments involving peroxide was investigated. The assay of pyruvate dehydrogenase activity in isolated renal mitochondria was employed as an example. Spontaneous peroxide-induced pyruvate decarboxylation competed significantly with enzymatic decarboxylation at peroxide concentrations greater than 50 μM. Corrected values for enzymatic decarboxylation could be obtained by subtracting spontaneous decarboxylation rates from rates obtained in the presence of mitochondria. At higher peroxide concentrations (>200 μM), reaction product accumulates (acetoacetate) to levels which may have regulatory effects on mitochondrial metabolism. The divalent cations, Ca2+ and Mg2+, both accelerate spontaneous peroxide-induced pyruvate decarboxylation while other components of the assay medium had an inhibitory effect on the reaction. The results are discussed in relation to the currently accepted reaction mechanism. Investigators who perform experiments involving reactive oxygen species should be familiar with this often overlooked reaction.

Use of autologous umbilical artery and vein for vascular reconstruction in the newborn

Autologous umbilical artery and vein were evaluated as vascular conduits in newborn lambs. Eight newborn lambs were delivered transabdominally under sterile conditions at term. The umbilical artery and vein were dissected from the cord and stored in culture media. On the same day, each lamb underwent bilateral superficial femoral artery transection and reconstruction. Nine arteries were reconstructed with autologous umbilical vein interposition grafts, five with umbilical artery interposition grafts, and two by primary native artery anastomosis. After the birth weight of the lambs quadrupled (37 to 45 days), they were killed and all grafts and anastomoses were examined grossly and histologically. At the conclusion of the study, both native artery anastomoses (2/2) were patent. Five umbilical vein (5/9) and two umbilical artery (2/5) autografts were also widely patent. Patent autografts retained an intact endothelium supported by a viable media. The nonpatent autografts had become atrophic remnants displaying histologic signs of early closure. Graft failures are attributed to the extreme vasoactive nature of the umbilical vessels. These preliminary results suggest that umbilical vessels may be useful as a vascular autograft if the vasoactive nature of these vessels can be overcome during the immediate perioperative period.