Hypothyroidism in adults with sickle cell anemia.

Persons with sickle cell anemia have several indications for transfusion of red blood cells. One of the complications of transfusion of red blood cells is iron overload. Iron overload has been associated with multiple endocrine abnormalities. We report herein three cases of hypothyroidism in adult individuals with sickle cell disease. All three patients were over the age of 45 years at the time of the diagnosis and had received multiple units of transfused red blood cells and had serum ferritin levels of greater than 6,000 ng/mL. All patients were diagnosed during times when they were critically ill. Replacement therapy was instituted in all cases; however, all three patients died shortly after the diagnosis of hypothyroidism was made. Congestive heart failure appeared to be a primary cause of death in all three patients. In the one patient in whom a postmortem examination was done, there was evident extensive fibrosis of the thyroid gland as well as extensive deposition of iron in the cells lining the thyroid follicles. We believe that this represents the first report of clinical hypothyroidism in patients with sickle cell anemia who have received multiple transfusions. Awareness of this condition is especially important given that congestive heart failure is common in sickle cell disease.

Age-related differences in response to neutrophil-mediated reperfusion injury in the neonatal piglet heart.

BACKGROUND: Neonatal hearts have altered adhesion molecule interactions in response to ischemia-reperfusion. How this affects myocardial function is unknown. METHODS: Isolated, buffer perfused 0- to 2-day (newborn) and 2-week piglet hearts were first subjected to 20-minute global, normothermic ischemia, followed by 45 minutes of reperfusion during which 150 x 10(6) newborn or 2-week neutrophils were infused. In some hearts, an antibody to SLe(x) (CSLEX-1) was infused with neutrophils during reperfusion. Hemodynamic variables, including left ventricular developed pressure (LVDP), were recorded at timed intervals. Neutrophil CD-18, L-selectin, and SLe(x) contents were measured by flow cytometry. RESULTS: Full recovery of LVDP was observed in newborn hearts receiving newborn or 2-week-old neutrophils. Recovery of LVDP was depressed (p < 0.01, ANOVA) in 2-week-old hearts receiving 2-week old, not newborn, neutrophils. Infusion of CSLEX-1 in 2-week-old hearts restored LVDP to baseline. Whereas flow cytometry showed higher (p < 0.01, Student's t test) CD-18 and L-selectin expression on newborn versus 2-week-old neutrophils, newborn neutrophils expressed lower (p < 0.01) SLe(x) levels. CONCLUSIONS: Initial "loose" neutrophil-endothelial selectin interactions are a necessary prelude to "firm" adhesion and reperfusion injury. Operations performed soon after birth may be better tolerated than when surgery is delayed; anti-SLe(x) preparations may prove beneficial when performing cardiac procedures on older infants.

Carnitine supplementation improves myocardial function in hearts from ischemic diabetic and euglycemic rats.

BACKGROUND: Nonischemic myocardial dysfunction in patients with diabetes mellitus appears to be attenuated with long-term L-carnitine therapy. The effect of acute L-carnitine supplementation on rat hearts from euglycemic and diabetic animals subjected to ischemia and reperfusion is investigated in this study. METHODS: Study rats had diabetes mellitus induced by streptozocin (65 mg/kg intraperitoneally), and control rats had injection of saline solution (n = 12 per group). About 1 month later, the hearts were suspended on a Langendorff apparatus and perfused with either standard buffered Krebs-Henseleit solution or this standard solution supplemented with L-carnitine (5 mmol/L). After stabilization, normothermic, zero-flow ischemia was instituted for 20 minutes followed by 60 minutes of reperfusion. There were four study groups (n = 6 per group): hearts that were from euglycemic rats and that were perfused with standard buffered Krebs-Henseleit solution (E-STD); hearts that were from diabetic animals and that were perfused with the same standard buffered solution (DM-STD); hearts taken from diabetic animals and perfused with L-carnitine-enriched solution (DM-CAR); and hearts taken from euglycemic rats and perfused with the enriched solution (E-CAR). RESULTS: At 60 minutes of reperfusion, left ventricular developed pressure was significantly better in hearts from both groups (diabetic and euglycemic) with carnitine supplementation (DM-CAR versus DM-STD and E-CAR versus E-STD, p < 0.01 for both, by analysis of variance). Left ventricular end-diastolic pressure was significantly lower in the DM-CAR group compared with all other groups (p < 0.01 by analysis of variance). CONCLUSIONS: These findings suggest that acute L-carnitine supplementation significantly improves the recovery of the ischemic myocardium in diabetic and euglycemic rats.

Lymph isolated from a regional scald injury produces a negative inotropic effect in dogs.

Large surface-area burns in patients have been associated with a severe impairment in cardiac performance, as evidenced by a decline in cardiac output. The mechanisms responsible for this profound myocardial dysfunction are largely unknown. We investigated the effects of lymph isolated from the scalded hind limb of dogs on regional myocardial blood flow, coronary vascular reactivity, and contractile performance. Dogs were instrumented with ultrasonic dimension crystals in the myocardium supplied by the left anterior descending (LAD) and by the left circumflex (LCx) coronary arteries. After cannulating a hind limb lymphatic, lymph was infused directly into the LAD before and after a 10-second 100 degrees C hind limb scald. Scalding alone did not alter myocardial contractile performance in the LAD or LCx regions, coronary artery blood flow, or systemic hemodynamics. Interestingly, postburn lymph infused into the LAD resulted in a 38% decline in LAD zone segment shortening (p < 0.01 vs baseline) that lasted throughout the 5-hour observation period. In contrast, segment shortening in the (control) LCx region was unaffected by postburn lymph injections into the LAD. Regional myocardial blood flow (radiolabeled microspheres) in the LAD and LCx regions was unchanged after scald injury or intracoronary injection of postburn lymph. In addition, LAD coronary artery vascular reactivity to acetylcholine and nitroglycerin was also unaffected by the regional thermal injury or by injection of lymph into the LAD. These data suggest that a regional scald injury results in the production and release of a potent myocardial depressant factor(s) that produces a direct negative inotropic effect on the canine myocardium.

Regulation of tissue plasminogen activator in sickle cell anemia.

Evidence of activation of the clotting system in individuals with sickle cell anemia (SCA) has been observed by several investigators. It has been suggested that the clotting and fibrinolytic systems may play a role in the pathophysiology of vaso-occlusion in SCA. We reported previously evidence of abnormal fibrinolytic activity as reflected in decreased releasable tissue plasminogen activator (t-PA) using a functional assay. We have examined the mechanism of the decreased functional releasable t-PA in individuals with SCA. We studied 12 patients with respect to releasable t-PA, fast acting inhibitor to t-PA (or PAI-1), and immunoreactive or antigenic t-PA. These SCA individuals were at their baseline states and not taking medications known to interfere with the fibrinolytic or clotting systems. We found that the mean releasable t-PA for the SCA individuals was 0.01 IU/ml of plasma with a standard error of mean (SEM) of 0.01. The mean releasable t-PA of 118 healthy normal controls was 0.70 IU/ml with SEM 0.10 (P less than .001). The mean level of fast-acting inhibitor to t-PA in unoccluded circulation of the SCA patients' plasma was 16.5 IU/ml with SEM of 3.54. The mean plasma levels of fast-acting inhibitor to t-PA in 56 healthy controls was 2.56 IU/ml with SEM of 0.29 (P less than .0001). The SCA patients had a mean baseline t-PA antigen level of 5.98 ng/ml with SEM of 1.72. The mean level of t-PA antigen of 78 healthy controls using the same technique was 4.3 ng/ml with SEM of 2.7 (not significant). The mean baseline functional t-PA for SCA individuals was 0.15 IU/ml with SEM 0.01 and the mean baseline functional t-PA for 118 controls was 0.17 IU/ml with SEM 0.10. These data suggest that the mechanism of decreased releasable t-PA in sickle cell anemia is related to an elevation of fast-acting inhibitor to t-PA and that antigenically t-PA is present in normal quantities in the baseline plasma in this population.

Mild preischemia hypothermia adversely affects postischemic myocardial function in the neonatal piglet heart.

BACKGROUND: During cardiac surgery, operative hypothermia has been shown to be beneficial in certain situations, although in children perioperative hypothermia has been associated with several physiologic alterations that have proven detrimental to their postoperative function. Little attention has been given to the effects of mild (34.5 degrees C) perioperative hypothermia on postischemic myocardial function in the pediatric population. It was hypothesized that mild hypothermia would be detrimental to postischemic ventricular function in the neonatal heart. METHODS: Neonatal (0-2 days old) piglets were subjected to mild perioperative hypothermia without rewarming (HT-only, n = 6), hypothermia followed by rewarming (HT-RW, n = 6), or continuous normothermia (NT, n = 8). The hearts were rapidly excised, suspended on an isolated perfusion apparatus, and allowed to spontaneously beat while being perfused with an asanguinous solution. All hearts were subjected to 20 min global, normothermic, zero-flow ischemia followed by 45 min oxygenated crystallite buffer reperfusion (I-R). RESULTS: Compared to that of NT piglets, there were significant (P < 0.05) reductions in recovery of left ventricular (LV) diastolic and systolic function following ischemia and reperfusion in HT-RW animals. When the hearts were rendered ischemic without first rewarming, the degree of myocardial dysfunction was not as severe. In contrast to the NT piglets, HT-RW animals demonstrated significant (P < 0.05) reductions in the final recovery of LV developed pressure (71 +/- 6 vs 105 +/- 6 in NT), LV rate pressure product (52 +/- 4 vs 102 +/- 9 NT), and LV end diastolic pressure (32 +/- 7 vs 3 +/- 1 in NT) following I-R. When compared to the HT-RW group, HT-only piglets did not exhibit significant differences in systolic function, although diastolic function was minimally altered initially as evidenced by the slight elevation of LV end diastolic pressure at 5 min, with reperfusion in the HT-only group (P < 0.05). CONCLUSIONS: In this newborn piglet model, mild hypothermia significantly reduces recovery of systolic and diastolic left ventricular function when followed by an episode of global myocardial ischemia-reperfusion only when the animals are returned to normothermia prior to the ischemic insult. When hypothermia is immediately followed by the ischemic event, left ventricular function is unaffected.