Elevated Endoxin-Like Factor Complicating a Multif etal Second Trimester Pregnancy: Treatment with Digoxin-Binding Immunoglobulin

Adair, Charles; Buckalew, Vardaman M.; Taylor, Kevin; Ernest, Joseph M.; Frye, Allison H.; Evans, Charles A.; Veille, Jean Claude

doi:10.1159/000169054

Cited by 54 publications

(54 citation statements)

References 8 publications

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“…Interestingly, plasma from patients with pregnancy-induced hypertension have elevated levels of a ouabain-like compound and marinobufagenin (70). Digibind, which has much greater affinity for ouabain than for the lipophilic marinobufagenin (91), also is reported to lower BP in patients with pregnancy-induced hypertension (1,31). In summary, these findings provide convincing evidence that a circulating Na ϩ pump inhibitor (a ouabain-like compound) plays a key role in some forms of hypertension.…”

Section: How Does Low-dose Ouabain Augment Contractility?mentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

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A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na ϩ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in Ϸ40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na ϩ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that ␣ 2 Na ϩ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the ␣ 2 Na ϩ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced ␣ 2 Na ϩ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced ␣ 2 Na ϩ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular ␣ 2 Na ϩ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.ouabain; Na ϩ pump; Na/Ca exchanger; Ca 2ϩ ; myogenic tone HYPERTENSION, DEFINED AS A diastolic blood pressure (BP) Ն 90 mmHg and/or systolic BP Ն 140 mmHg, is endemic in Westernized societies. This is a very important public health issue because hypertension is a major risk factor for premature death and disability from heart attack, heart failure, stroke, and many other afflictions (16,59). In the United States, alone, Ϸ20% of the population (i.e., Ϸ50 million individuals) are hypertensive; moreover, more than half of all individuals over the age of 60 years have hypertension. In a small fraction of cases, the hypertension is due to specific causes, such as renal vascular disease or excessive secretion of aldosterone (primary aldosteronism) or catecholamines (pheochromocytoma). The vast majority (Ϸ90%) of patients, however, have elevated BP of unknown cause; hence the terms, primary or essential hypertension. The immediate cause for the elevated BP in nearly all chronic hypertensive persons is excessive narrowing of the small (resistance) arteries. Nevertheless, a key question in any discussion of hypertension is: What specific mechanisms actually lead to the abnormal arterial constriction and elevation ...

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Section: How Does Low-dose Ouabain Augment Contractility?mentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

View full text Add to dashboard Cite

show abstract

“…Although this change was of borderline statistical significance, it is similar to the increase in creatinine clearance we observed in a patient with preeclampsia treated with DIF prior to delivery. 10 The exact mechanism of this effect is not known, but is compatible with reversal of intrarenal vasoconstriction by DIF.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,[13][14][15][16][17][18] The strongest evidence for a causal role of EDLF in preeclampsia is the anecdotal reports that digoxin-binding immunoglobulin lowers blood pressure in preeclampsia. 9,10 The present trial represents the next step in formally evaluating the role of EDLF and attenuation of EDLF in the preeclamptic patient. We recognize that this trial has a number of limitations, not the least of which is that the study was performed in the postpartum, as necessitated by safety considerations.…”

Section: Discussionmentioning

confidence: 99%

“…Goodlin 9 reported that DIF lowered blood pressure in his index subject, and we reported similar results in one additional subject. 10 Because of these encouraging findings, we performed a prospective, randomized, double-blind, placebo-controlled trial of the effect of DIF on blood pressure in subjects with severe preeclampsia. To avoid fetal exposure to the unknown effects of DIF, the study drug was administered during the immediate postpartum period.…”

Section: Introductionmentioning

confidence: 99%

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The hemodynamic effects of intravenous digoxin-binding fab immunoglobulin in severe preeclampsia: a double-blind, randomized, clinical trial

et al. 2009

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Objective: An endogenous digitalis-like factor (EDLF) has been implicated in the pathophysiology of preeclampsia (PE). This hypothesis is supported by two cases of preeclampsia in which administration of digoxin immune Fab (DIF) reduced mean arterial pressure (MAP). Study Design: To study this observation further, we performed a double-blind, placebo-controlled, randomized clinical trial to examine the effects on MAP of intravenous DIF given after delivery in 26 subjects with severe preeclampsia. Treating obstetricians were blinded to subject assignment and were allowed to use standard antihypertensive drugs during the trial. Results: The primary outcome, a significant difference in blood pressure between the two groups over the 24-h period of observation after the intervention, was not supported. However, mean MAP was significantly lower in the DIF-treated subjects for the first 4 h after therapy as compared with controls (P ¼ 0.05). Six subjects (46.2%) in the placebo arm were given conventional antihypertensive medications by their obstetrician for blood pressure >160 mm Hg systolic or >110 mm Hg diastolic, compared with zero subjects in the treatment arm (P ¼ 0.01). A trend towards increased creatinine clearance was observed in DIF-treated subjects (137.6 ± 42.6 versus 104.1 ± 43.4, P ¼ 0.07). Conclusion: These results support the hypothesis that EDLF contributes to the elevated blood pressure in preeclampsia and suggests a possible role for DIF as a treatment for this condition.

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“…[24][25][26] While the evidence for DLF mediation of the hypertension of pre-eclampsia is limited, it is of interest to note that women with preeclampsia treated with a digoxin Fab fragment (which binds and inactivates the DLF) showed marked reductions in blood pressure. 27,28 It is possible that the increase of DLF levels in response to the OGTT was not a direct consequence of insulin but was caused by a secondary factor. While these experiments do not implicate any such factor, the difference in timing between FFA and DLF responses makes FFA unlikely mediators of the DLF response.…”

Section: Insulin Resistance and Dlfmentioning

confidence: 99%

Digitalis-like factor response to hyperinsulinemia in human pregnancy, a model of insulin resistance

et al. 2002

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Insulin resistance is strongly associated with hypertension and is postulated to participate in the elevation of blood pressure, although the mechanisms involved are not understood. Recently, we reported that acute increases in plasma insulin levels in normal subjects resulted in increased serum levels of a sodium pump inhibitor, termed the digitalis-like factor (DLF), which has been implicated in both experimental and essential human hypertension. This study looked at the DLF response to hyperinsulinemia, achieved by an oral glucose tolerance test (OGTT), in the setting of a naturally occurring and self-resolving state of human insulin resistance, during third-trimester pregnancy. This model allowed us the further opportunity to compare the DLF response to insulin in the same subjects postpartum, after resolution of their insulin resistance. Administration of an OGTT during pregnancy and postpartum in the same subjects elicited a comparable serum glucose response but a significantly greater insulin response during third-trimester pregnancy, consistent with diminished insulin sensitivity (integrated insulin response during pregnancy: 1611 7 236 vs postpartum: 685 7 101 pmol/l, P ¼ 0.004). The time courses of the glucose and insulin responses were identical whether women were pregnant or not. Plasma free fatty acids fell significantly and to a comparable degree during pregnancy and postpartum, but the response was slower during pregnancy. DLF levels increased in response to oral glucose in both pregnant and nonpregnant states. The response was more rapid during pregnancy than after. These findings showed that the increment of insulin induced by oral glucose during pregnancy caused a more rapid rise in circulating DLF levels than it did during the nonpregnant state. At the same time, the response of circulating fatty acids to glucose is retarded during pregnancy. This suggests that the insulin resistance of pregnancy impairs insulin's influence on intermediary metabolism but not its influence on DLF. As a vasoactive substance, DLF might contribute to the hypertension characteristic of insulin-resistant states.

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Elevated Endoxin-Like Factor Complicating a Multif etal Second Trimester Pregnancy: Treatment with Digoxin-Binding Immunoglobulin

Abstract: We report a case of a second trimester multifetal pregnancy with preeclampsia associated with an elevated digoxin-like immune factor. Due to the remoteness from viability the patient was offered therapy with digoxin-binding immunoglobulin. No untoward maternal effects were noted.

Cited by 54 publications

References 8 publications

How does salt retention raise blood pressure?

How does salt retention raise blood pressure?

The hemodynamic effects of intravenous digoxin-binding fab immunoglobulin in severe preeclampsia: a double-blind, randomized, clinical trial

Digitalis-like factor response to hyperinsulinemia in human pregnancy, a model of insulin resistance

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