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The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI) < 9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 ± 7.1 weeks gestation, with mean BDI scores of 16.4 ± 9.6, compared to a mean treatment response BDI of 6.9 ± 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These novel data on SSRI daily dose in pregnancy parallels the extant literature with tricyclic antidepressants (TCA). Further work to determine the predictors of dose adjustments will provide guidelines for minimizing fetal exposure to both medication and maternal mental illness. Depression and Anxiety 11:51–57, 2000. © 2000 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients., Methods: The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools-a 3-minute video and 1-page checklist-delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to "make one positive change" in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period., Results: EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of β-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT ( P =0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups., Conclusions: A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03334188.

Background: Heart failure with reduced ejection fraction (HFrEF) benefits from initiation and intensification of multiple pharmacotherapies. Unfortunately, there are major gaps in the routine use of these drugs. Without novel approaches to improve prescribing, the cumulative benefits of HFrEF treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients., Hypothesis: Encouraging patients to engage providers in HFrEF prescribing decisions will improve the use of guideline-directed medical therapies., Design: The Electronically delivered, Patient-activation tool for Intensification of Chronic medications for Heart Failure with reduced ejection fraction (EPIC-HF) trial randomizes patients with HFrEF to usual care versus patient-activation tools-a 3-minute video and 1-page checklist-delivered prior to cardiology clinic visits that encourage patients to work collaboratively with their clinicians to intensify HFrEF prescribing. The study assesses the effectiveness of the EPIC-HF intervention to improve guideline-directed medical therapy in the month after its delivery while using an implementation design to also understand the reach, adoption, implementation, and maintenance of this approach within the context of real-world care delivery. Study enrollment was completed in January 2020, with a total 305 patients. Baseline data revealed significant opportunities, with <1% of patients on optimal HFrEF medical therapy., Summary: The EPIC-HF trial assesses the implementation, effectiveness, and safety of patient engagement in HFrEF prescribing decisions. If successful, the tool can be easily disseminated and may inform similar interventions for other chronic conditions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The efficacy of cardiac screening programs for individuals in competitive athletics and high-risk occupations such as commercial and military aviation continues to be highly debated. For the past 12 yr, all United States Air Force (USAF) pilot applicants have undergone screening echocardiography., Methods: All available studies were reviewed for disqualifying (DQ) diagnoses. Findings were analyzed and compared to current USAF waiver policy., Results: Between inception in March 1994 and 01 September 2006, there were 20,208 screening echocardiograms performed. Of these, 294 (1.45%) were initially read as disqualifying. The most common diagnoses were bicuspid aortic valves with mild or less aortic insufficiency (N = 154, 0.76%), mitral valve prolapse with mild or less mitral regurgitation (N = 51, 0.25%), and trileaflet aortic valve with mild aortic insufficiency (N = 58, 0.29%). Evolution of USAF waiver policy has now rendered these diagnoses waiverable for entry into pilot training. Under current policy, 285/294 would be eligible for an unrestricted waiver, leaving only 9 individuals "DQ/no-waiver" (0.0445%). There were no cases of hypertrophic cardiomyopathy. Although the number of USAF pilot applicants has increased in recent years, the DQ/no-waiver rate has actually decreased, with only a single DQ/no-waiver finding since 2004 (N = 5802 studies; 0.0172%)., Discussion: The infrequency of positive findings in this large cohort of screening echocardiography raises questions about the appropriateness of such programs. Under current USAF policy, it is not efficacious to perform screening echocardiography on all pilot applicants.

Stimulated production of reactive oxygen species (ROS) by plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidases (Nox) in non-phagocytic cells regulates a number of biological processes including growth, vessel tone, and oxygen sensing. The purpose of this study was to investigate H(2)O(2)-stimulated ROS production in primary adult cardiac fibroblasts (CF). Results demonstrate that CF express an H(2)O(2)-inducible oxidant generating system that is inhibitable by diphenylene iodonium (DPI) and sensitive to antioxidants. In addition to H(2)O(2), generation of ROS was stimulated potently by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and arachidonic acid (AA) in a protein kinase C-independent manner. Pretreatment with arachidonyl trifluoromethyl ketone was nearly as effective as DPI at reducing H(2)O(2)- and OAG-stimulated oxidant generation indicating a central role for phospholipase A(2) (PLA(2)) in this signaling pathway. Co-stimulation with H(2)O(2) and OAG did not increase ROS generation as compared to OAG alone suggesting both agonists signal through a shared, rate-limited enzymatic pathway involving PLA(2). Co-stimulation with H(2)O(2) and AA had additive effects indicating these two agonists stimulate oxidant production through a parallel activation pathway. Reverse transcriptase-coupled polymerase chain reaction and Western blotting demonstrate primary cardiac fibroblasts express transcripts and protein for Nox4, p22, p47, and p67 phox. Transfections with Nox4 small inhibitory ribonucleic acid oligonucleotides or p22 phox antisense oligonucleotides significantly downregulated stimulated Nox activity. Inhibitors of nitric oxide synthases were without effect. We conclude adult CF express Nox4/p22 phox-containing oxidant generating complex activated by H(2)O(2), OAG, and AA through a pathway that requires activation of PLA(2).

The introduction of lithium salts almost a century ago and the subsequent approval of lithium carbonate for the treatment of patients with bipolar disorder represent one of the cornerstones of modern psychopharmacology. The onset of bipolar disorder in women often occurs during the childbearing years, which complicates the treatment decisions secondary to the possibility of conception while taking medication. The establishment of the lithium registry for fetal teratogenesis in the late 1960s ushered in a heightened level of concern for the use of lithium during the reproductive years; although, in the years to come, it has become apparent that alternative pharmacologic treatments for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In this paper, the available data on the use of antimanic medications during pregnancy and lactation are reviewed with an emphasis on providing a realistic risk/benefit assessment for medication selection and management of these patients. Treatment strategies are discussed for (1) women who are contemplating pregnancy (2) women who inadvertently conceive while taking medications (3) women who choose to become pregnant while taking medication, and (4) women who intend to breastfeed while taking medications.

This study examined the effects of chronic surgical ventricular sympathectomy on the relationships between left ventricular mechanical performance, coronary blood flow, and exercise workload in sham-operated control dogs and dogs which had been ventricular sympathectomized 8 wk earlier. During exercise, left ventricular global contractile state was less in sympathectomized ventricles than in control ventricles, as indicated by reduced systolic pressure and maximal rate of pressure generation. Regional contractile shortening was not different. Heart rate was significantly elevated in sympathectomized ventricles. Therefore, peak systolic pressure-heart rate product and tension-time index were not different in sympathectomized ventricles compared to control ventricles. However, at each level of exercise, mean coronary flow in sympathectomized ventricles was reduced by about 50% compared to control values. The slopes of coronary flow on pressure-rate product and tension-time index were also reduced. No difference in left ventricular oxygen extraction between control and sympathectomized hearts were observed. Thus, chronic ventricular sympathectomy altered the relationships between coronary flow and oxygen consumption, on the one hand, and ventricular oxygen-dependent performance and whole-body exercise level, on the other hand.

The ability of the systemic circulation to maintain cardiac output during decreases in arterial pressure was evaluated in conscious dogs with intact reflexes (n = 8) and during pharmacological blockade of the autonomic nervous system, angiotensin II formation, and arginine vasopressin (n = 6). Cardiac output was measured electromagnetically, and aortic pressure was controlled via a gravity reservoir connected to a carotid artery. When aortic pressure was decreased in either small steps to approximately 60% of control, or decreased in a single square-wave step to 75% of control and maintained for 2 h, cardiac output decreased to the same or a greater extent in both control and areflexic dogs. Thus total peripheral resistance did not decrease, and autoregulation of the cardiac output did not occur in response to short-term (less than or equal to 2 h) decreases in arterial pressure, even in the absence of the major pressor systems. After long-term (greater than 8 h) decreases in arterial pressure to 75% of control in five dogs with all reflexes intact, significant autoregulation of the cardiac output occurred. The relationship between the gain of blood flow autoregulation and the corresponding values of mixed venous oxygen tension suggests that whole body autoregulation results when oxygen extraction reserve becomes limited.

Hindlimb vascular bed pressure-flow relationships were evaluated in seven conscious dogs using a newly developed controlled-flow perfusion technique. For controlled-flow perfusion, blood was diverted from a common carotid artery to a roller pump for perfusion of the left hindlimb vascular bed via an artificial vascular graft anastomosed to the left external iliac artery. An occlusion cuff positioned around the external iliac artery proximal to the graft arrested normal hindlimb blood flow during perfusion. Collateral flow was minimized by ligating all other major arteries supplying the left hindlimb. Hindlimb perfusion pressure, measured via the left deep femoral artery, decreased to a plateau value of 19.7 +/- 3.4 mmHg when pump flow was zero. Pressure-flow relationships were evaluated while the dogs were at rest by changing flow in small "square-wave" steps for 3 min each and measuring the steady-state perfusion pressure at each step. The hindlimb was perfused over a wide range of flows (25-450 ml/min) that resulted in perfusion pressures ranging from 40 to 175 mmHg. The hindlimb pressure-flow relationship obtained was indicative of net passive vascular behavior. That is, resistance to flow decreased with increases in flow, such that a curvilinear pressure-flow relationship occurred that was convex to the pressure axis. We conclude that the hindlimb circulation of resting conscious dogs can be perfused using controlled-flow perfusion techniques. These techniques can also be applied to other vascular beds and should be useful for evaluating peripheral vascular responses to drugs and reflexogenic alterations.

During submaximal exercise, an alpha adrenergic vasoconstriction that opposes metabolic dilation exists in the coronary circulation. Fifteen dogs were given i.c. injections of prazosin (0.5 mg) or yohimbine (0.7 mg) to determine the participation of alpha 1 and alpha 2 adrenoceptors in the vasoconstriction during exercise. All dogs were chronically instrumented to measure left circumflex blood flow, heart rate, regional left ventricular function and global left ventricular function. The experimental protocol consisted of a graded exercise regimen during which, at the highest level of exercise an alpha antagonist was given i.c. Exercise significantly increased heart rate, left ventricular pressure, dP/dt, systolic shortening and rate of shortening, and coronary blood flow. After the prazosin injection there was an increase in circumflex blood flow (25 +/- 3%) as well as regional (38 +/- 6%) and global (20 +/- 3%) contractile function. However, there was no change in circumflex blood flow or myocardial function after yohimbine. These data indicate that during exercise the sympathetic constrictor tone in the coronary circulation is mediated primarily by alpha 1 adrenoceptors, with little or no involvement from alpha 2 adrenoceptors.

We evaluated the efficiency of blood flow autoregulation of the hind-limb vascular bed of eleven conscious dogs during: resting conditions; graded levels of treadmill exercise; and increases in oxygen consumption produced by the administration of 2,4-dinitrophenol (DNP). Blood flow to the left hind limb was measured with an electromagnetic flow probe on the left external iliac artery. Hind-limb perfusion pressure was measured from a catheter in the deep femoral artery and was controlled via an externally inflatable occlusion cuff positioned just distal to the flow probe. Arterial pressure was measured in the abdominal aorta. Experiments were performed 5-16 days after instrumentation. Hind-limb pressure-flow (P-F) relationships were evaluated by decreasing hind-limb perfusion pressure in 4-5 small sequential 'square-wave' steps of 10-15 mmHg each while measuring flow. Each step decrease in perfusion pressure was maintained for 2 min. The efficiency of autoregulation was quantified by calculating the closed-loop gain of flow regulation (Gc) at each decrement in perfusion pressure utilizing the equation: Gc = 1-[(F0-Fn/F0)/(P0-Pn/P0)] where F0 and P0 are the starting (control) flows and pressures prevailing prior to decreasing perfusion pressure, and Fn and Pn are the new flows and pressures at each decrement in perfusion pressure. A Gc value less than 0 indicates a predominantly passive P-F relationship, while a Gc of 1 is perfect autoregulation of flow. When the dogs were at rest, decrements in hind-limb perfusion pressure were accompanied by almost equivalent decreases in flow, i.e. no autoregulation occurred, and Gc averaged -0.177 +/- 0.044 over the pressure range from 100-40 mmHg. During all levels of treadmill exercise (on gradients of 0, 7, or 21%), however, positive Gc values were found that averaged from 0.258 +/- 0.046 at a gradient of 0% to 0.392 +/- 0.041 at a gradient of 21% and were significantly different from Gc values found during rest at perfusion pressure ranges from 90-40 mmHg. The administration of DNP directly into the hind-limb circulation increased hind-limb blood flow from 199 to 481 ml/min. In the presence of DNP, Gc values were positive over perfusion pressure ranges from 100-40 mmHg and averaged 0.473 +/- 0.054. These data demonstrate that hind-limb blood flow is not autoregulated in resting dogs, but that significant autoregulation is manifest during conditions that increase oxygen consumption.(ABSTRACT TRUNCATED AT 400 WORDS)