Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation.

Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.

Hidradenoma papilliferum with mixed histopathologic features of syringocystadenoma papilliferum and anogenital mammary-like glands: report of a case and review of the literature.

Hidradenoma papilliferum of the anogenital region was previously believed to originate from apocrine glands but has recently been accepted as originating from anogenital mammary-like glands. We describe a case of hidradenoma papilliferum with mixed features of syringocystadenoma papilliferum and mammary-like glands from the left labia majora of a 25-year-old woman. Histopathologically, the lesion showed an epithelial lining with apocrine secretion, and like syringocystadenoma papilliferum, the lesion extended from the epithelium as invaginations into the dermis. Adjacent to this lesion were ductal and glandular structures resembling normal mammary tissue. This review of the literature highlights the heterogeneity and complexity of lesions arising from anogenital mammary-like glands, and this case serves as further documentation of the association between anogenital mammary-like glands and hidradenoma papilliferum.

Relationship of adiponectin to endogenous GH pulse secretion parameters in response to stimulation with a growth hormone releasing factor.

OBJECTIVE: Obesity is associated with both reduced growth hormone (GH) and adiponectin. However, the relationship between adiponectin and parameters of endogenous GH secretion remains unknown. The aim of this study was to determine the relationship between total and high molecular weight (HMW) adiponectin and parameters of endogenous pulsatile GH secretion and the effects of tesamorelin, a synthetic GH releasing hormone (GHRH(1-44)), on total and HMW adiponectin. DESIGN: A 2-week interventional study with tesamorelin was conducted at an academic medical center in 13 men with BMI 20-35 kg/m(2). Overnight frequent blood sampling and measurement of total and HMW adiponectin at baseline and after treatment were performed to assess the effects of augmenting endogenous pulsatile GH secretion. RESULTS: Total, but not HMW, adiponectin was positively associated with log(10)Peak GH area (r=+0.73; P=0.005), basal GH secretion (r=+0.67; P=0.01), and total GH production (r=+0.57; P=0.04), but was not associated with the number of secretion events (P=0.85). Two-week treatment with tesamorelin increased endogenous GH release and IGF-1, but neither total (change -0.16±0.64; P=0.40), nor HMW (change +0.03±0.70; P=0.87) adiponectin changed significantly with treatment. Sub-analyses in overweight and obese men yielded similar results. CONCLUSIONS: Our study demonstrates a strong relationship between specific parameters of endogenous GH pulsatility and adiponectin. However, short-term augmentation of GH pulsatility over 2-weeks does not change adiponectin. Therefore, the relationship between GH and adiponectin is most likely mediated by specific covariates related to adiposity or other factors.

Comparison of functional capacity in patients with end-stage heart failure following implantation of a left ventricular assist device versus heart transplantation: results of the experience with left ventricular assist device with exercise trial.

BACKGROUND: Use of a permanent left ventricular assist device (LVAD) has been proposed as an alternate treatment of patients with end-stage heart failure. The purpose of this study was to compare the functional capacity of patients following implantation of a LVAD vs heart transplant (HTx). METHODS: Eighteen patients from 6 centers who received an intracorporeal LVAD as a bridge to HTx underwent treadmill testing 1 to 3 months post-LVAD and again post-HTx. Baseline and peak measurements, including oxygen consumption, blood pressures, and respiratory rate were made during each treadmill test. RESULTS: Peak oxygen consumption was 14.5+/-3.9 ml/kg/minute post-LVAD and 17.5+/-5.0 ml/kg/minute post-HTx (p < .005). The percentage of the predicted peak oxygen consumption based on gender, weight, and age was 39.5%+/-5.5% post-LVAD and 47.7%+/-10.9% post-HTx (p < .005). Exercise duration was lower post-LVAD than post-HTx (10.3+/-4.2 minute vs 12.5+/-5.4 minute, p < .05). After LVAD implantation, peak total oxygen consumption correlated with peak LVAD rate and output. Eight patients reached an LVAD rate of 120 beats per minute (bpm) before the conclusion of exercise, the maximum rate for the outpatient electric device. The peak respiratory exchange ratio post-LVAD was 1.15+/-0.22 and post-HTx was 1.15+/-0.18, consistent with a good effort in both groups. CONCLUSIONS: Patients demonstrated a lower functional capacity post-LVAD than post-HTx. For some patients functional capacity post-LVAD may be improved by a higher maximum LVAD rate and output.

Predicting children's sunscreen use: application of the theories of reasoned action and planned behavior.

BACKGROUND: Skin cancer remains the most common form of cancer in the United States despite the fact that most cases can be prevented by limiting sun exposure. Childhood and adolescence are periods of life during which prolonged sun exposure is particularly common. Accordingly, promoting sun-protective behaviors during these formative years can be of critical importance in preventing skin cancer. The present study applied the theories of reasoned action and planned behavior to the understanding of children's sunscreen use. Based on these theories, it was hypothesized that attitudes, subjective norms, and perceived behavioral control would be related to intentions to use sunscreen, which, in turn, would be related to actual sunscreen use. METHODS: Questionnaires measuring sun-related attitudes, beliefs, perceived control, and intentions were administered to 199 fourth graders (ages 9 to 13, mean = 10.3) attending public schools in Florida. Self-report measures of sun-related behavior were administered to the same subjects 1 month later. RESULTS: Results of correlational analyses were consistent with study hypotheses. Higher rates of sunscreen use at follow-up were predicted by stronger intentions to use sunscreen assessed 1 month previously. In addition, stronger intentions to use sunscreen were found to be related to more favorable attitudes toward sunscreen use, stronger beliefs that peers and parents favored sunscreen use, and greater perceptions of personal control in using sunscreen. Path and multiple regression analyses identified direct and indirect relationships among study variables that partially confirmed those predicted by the theories and provided support for the use of an expanded model that included perceived behavioral control. CONCLUSIONS: The present study confirmed hypotheses derived from the theories of reasoned action and planned behavior regarding the relation of attitudes, subjective norms, and perceived behavioral control to sunscreen use among fourth graders. In addition to their theoretical significance, these findings suggest ways to intervene at the individual, classroom, and family levels to promote greater sunscreen use in this age group.

Mivacurium apnoea: a trap for the unwary.

We present a case of unanticipated postoperative apnoea in a patient with associated medical illness to illustrate the diagnostic difficulty that can arise in the detection and subsequent management of mivacurium apnoea. A high index of suspicion is essential in the presence of concomitant medical conditions that may cause prolonged apnoea. To our knowledge, no report exists documenting the unanticipated occurrence of mivacurium apnoea in a patient with previously undiagnosed pseudocholinesterase deficiency and concomitant medical illness who has previously undergone 'balanced' general anaesthesia.

Risks of subsequent pregnancies on mother and newborn in female heart transplant recipients.

BACKGROUND: Female heart transplant recipients are able to carry pregnancies successfully. This study evaluates the effect of subsequent pregnancies on newborn and maternal outcomes and graft survival. METHODS: Subjects were identified through a previously reported multicenter study, case reports from literature review, and recipients entered in the National Transplantation Pregnancy Registry. A retrospective analysis was completed of 35 heart transplant recipients with first pregnancies (FP) and 12 who had one or two additional pregnancies (P>1). Newborns were assessed for gestational age, neonatal birth weight, and complications. Maternal data included pregnancy outcome, peripartum complications, including infection and rejection, current graft function, and recipient survival. RESULTS: Forty-seven pregnancies (35 FP and 12 P>1) from 35 heart transplant recipients were studied. FP outcomes included 26 live births (one set of twins), four miscarriages, and six therapeutic abortions, whereas P>1 outcomes included 11 live births (one set of twins), and two miscarriages. There was no significant difference between mean birth weights (2353+/-986 gm vs 2588+/-521 g, P>1 vs FP; mean+/-SD; p=NS) or prematurity incidence (<37 weeks; 50% vs 40%; p=NS) for the live-born infants. Compared with the FP group, there was a trend toward increased neonatal complications in P>1 (40% vs 12%; p=NS). Complications were significantly more common in premature newborns compared with full-term newborns (33% vs 5%; p < 0.05). No structural malformations were identified in the live-born infants. Maternal complication rates were the same in both groups (40%). Of 28 recipients available for follow-up, the maternal survival rate was 75% for the FP group and 89% for the P> group. Mean rejection rate per year was slightly increased after pregnancy in the P>1 group. Surviving recipients had similar graft function by echocardiographic left ventricular ejection fraction. CONCLUSIONS: Post-heart transplantation pregnancies often have successful outcomes, but there is a high incidence of prematurity and low birth weight. Subsequent pregnancies do not seem to significantly increase the incidence of complications in either the newborn or mother or increase graft rejection or failure. Larger studies of posttransplantation pregnancies may provide more definitive information.

Cloning and expression analysis of murine phospholipase D1.

Activation of phosphatidylcholine-specific phospholipase D(PLD) occurs as part of the complex signal-transduction cascade initiated by agonist stimulation of tyrosine kinase and G-protein-coupled receptors. A variety of mammalian PLD activities have been described, and cDNAs for two PLDs recently reported (human PLD1 and murine PLD2). We describe here the cloning and chromosomal localization of murine PLD1. Northern-blot hybridization and RNase protection analyses were used to examine the expression of murine PLD1 and PLD2 ina variety of cell lines and tissues. PLD1 and PLD2 were expressed in all RNA samples examined, although the absolute expression of each isoform varied, as well as the ratio of PLD1 to PLD2. Moreover, in situ hybridization of adult brain and murine embryo sections revealed high levels of expression of individual PLDs in some cell types and no detectable expression in others. Thus the two PLDs probably carry out distinct roles in restricted subsets of cells rather than ubiquitous roles in all cells.

Effects of exercise during long-term support with a left ventricular assist device. Results of the experience with left ventricular assist device with exercise (EVADE) pilot trial.

BACKGROUND: Long-term implantation of a left ventricular assist device (LVAD) may be a future alternative treatment for end-stage heart failure. The objective of the present study was to determine the hemodynamic effects of supine bicycle exercise and functional capacity during upright treadmill exercise in 10 patients after LVAD implantation placed for refractory heart failure as a bridge to cardiac transplantation. METHODS AND RESULTS: With supine bicycle exercise, 46 +/- 25 days after device placement, heart and LVAD rates increased in parallel from 87 +/- 12 to 117 +/- 14 bpm and 82 +/- 18 to 107 +/- 21 bpm, respectively. Peak O2 consumption was 8.2 +/- 1.7 mL O2.kg-1.min-1. Fick Systemic blood flow rose from 5.0 +/- 1.2 to 7.8 +/- 2.5 L/min. Right atrial and pulmonary capillary wedge pressures increased from 6 +/- 4 and 5 +/- 3 mm Hg to 12 +/- 5 and 13 +/- 8 mm Hg, respectively. End-diastolic left ventricular dimension increased from 3.9 +/- 1.3 to 4.8 +/- 1.6 cm; however, right ventricular dimension decreased from 3.2 +/- 1.0 to 2.3 +/- 0.9 cm. With upright treadmill exercise, peak O2 consumption was 14.1 +/- 2.9 mL O2.kg-1.min-1. CONCLUSIONS: This study indicates that exercise during long-term LVAD support is safe and is not limited by right heart decompensation. It also justifies a larger study to examine how exercise after LVAD implantation compares with that after cardiac transplantation.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Female solid organ recipients with good graft function generally tolerate pregnancy well. However, the combination of mother, fetus, transplanted organ, and immunosuppressive and other medications increases the complexity of management and raises the specter of adverse outcomes. For the mother, considerations include the nature of the original disease (i.e. genetic risk of transmission), co-morbid conditions which increase pregnancy risk (i.e. hypertension, diabetes, renal insufficiency), and long-term maternal prognosis. For the fetus, questions include the adequacy of maternal physiology (cardiac, renal, glycernic control, etc.), exposure to medications, and exposure to infectious agents. The transplanted organ must accommodate the increased workload of pregnancy and the needs of the fetus. The delicate balance between immunosuppression and rejection may be altered by the pregnancy. The impact of pregnancy on recurrent disease can also be an issue. Medication issues include changes in drug pharmacokinetics and the potential for adverse effects on the fetus. These effects could include chromosomal aberrations, structural malformations, organ-specific toxicity, intrauterine growth retardation, and immune system development. For female kidney recipients there are sufficient data to demonstrate a direct relationship between creatinine levels before and during pregnancy and risk of graft loss in the postpartum period. Pregnancy itself does not appear to adversely affect stable graft function. Among liver recipients, those with recurrent viral hepatitis may have deterioration of graft function with subsequent pregnancies. These recipients should be apprised accordingly, as maternal deaths have occurred in this setting. Postpartum depression and potential for medication noncompliance require vigilance. The safety of pregnancy from the NTPR analysis to date has been largely derived from the experience with CsA-based regimens. For recipients on CsA there have been good maternal outcomes without any specific or predominant malformation patterns in the offspring. For the general population, malformations occur in approximately 3% of live births. To date, there is no indication that this incidence has increased despite the complex medical regimens of transplant recipients. Data are accruing with tacrolimus and Neoral. Continuing data entry and continued follow-up of off-spring will allow for further recommendations, especially in light of the new medications and combinations. Recipients should be advised to wait one to 2 years after transplant before considering pregnancy. Those with stable graft function, and with no rejection, graft dysfunction, or deterioration should still be apprised of the high risk of prematurity and low birthweight, although maternal risks appear low. These are high-risk pregnancies, requiring close communication and cooperation between the high-risk obstetrician and the transplant team. The use of the FDA pregnancy categories should not be the sole reason for choosing a particular immunosuppressive drug. Agents such as Neoral and tacrolimus would appear to offer some advantage as blood levels can be measured. At present, no safety guidelines can be given for mycophenolate mofetil, OKT3, or ATG. Identification of prepregnancy factors predictive of higher risks and appropriate counseling and management guidelines are major NTPR goals, and depend on the continued assistance and cooperation of the transplant community.

Anterograde perfusion in acute limb ischemia secondary to vascular occlusive cardiopulmonary support.

Cardiopulmonary support (CPS) can resuscitate a patient with circulatory collapse during high-risk interventional procedures, although vascular complications may accompany its use. We report a patient with cardiogenic shock secondary to myocardial infarction who required extended CPS support associated with acute infarct-related coronary artery angioplasty and stent placement. Leg ischemia due to an occlusive cannula was resolved using a percutaneous anterograde perfusion device. In general, such devices may have application in patients dependent on mechanical support associated with limb ischemia.

Diagnosis and treatment of complications in patients implanted with a TCI left ventricular assist device.

Currently used left ventricular assist devices allow chronic mechanical cardiac support in the patient with end-stage heart failure. Recognition and treatment of problems uniquely associated with this device may be increasingly important for the invasive cardiologist as application of this technology becomes more prevalent.

Physiology of the native heart and Thermo Cardiosystems left ventricular assist device complex at rest and during exercise: implications for chronic support.

Studies of patients supported with a left ventricular assist device have considered determinants of acute survival emphasizing the role of right heart function. In patients with refractory heart failure awaiting heart transplantation, chronic left ventricular assist device implantation may provide an opportunity for rehabilitation before surgery if hemodynamics are adequate at rest and during activities of daily life. For the assessment of the efficacy of the left ventricular assist device in this setting, four patients in whom the HeartMate pneumatic left ventricular assist device had been implanted were tested during graded supine bicycle exercise with Doppler echocardiography interrogation and central hemodynamic measurements. Patients with left ventricular assist device increased total left ventricular-left ventricular assist device complex output with exercise as Fick cardiac output increased from 5.7 +/- 1.5 to 8.6 +/- 3.1 L/min (mean +/- standard deviation). In two patients, peak left ventricular assist device rate and output were either present at the start of exercise or reached at mid-exercise and were associated with abrupt increases in left ventricular filling pressures (pulmonary capillary wedge pressure = 9 to 27 mm Hg and 12 to 24 mm Hg, respectively). During exercise, left ventricular end-diastolic size and pressure increased as right ventricular dimensions decreased or remained the same (patients 1, 3, and 4: 1.7 to 1.8 cm, 4.7 to 3.9 cm, and 2.6 to 1.8 cm, respectively) despite increased right atrial filling pressures, implying a decrease in functional right ventricular diastolic compliance. Although the left ventricular assist device functioned as a series pump at rest, Fick cardiac output exceeded left ventricular assist device output during exercise consistent with parallel ejection of the left ventricle through the native aortic valve. During exercise, residual left ventricular function may contribute to the hemodynamic response by (1) active filling of the left ventricular assist device to reduce filling time and to overcome left ventricular assist device inflow cannula impedance, (2) augmentation of total cardiac output with parallel ejection out of the native aortic valve, or (3) reduction of ventricular interaction-related changes in functional right ventricular diastolic compliance. When residual left ventricular function is sufficient, hemodynamics with exercise may be limited by peak left ventricular assist device rate. Although right ventricular function may affect acute postoperative survival, residual left ventricular function and peak left ventricular assist device rate may be important determinants of exercise performance during chronic implantation. A preliminary model of factors affecting the "left ventricular-left ventricular assist device complex" performance at rest and during exercise is presented.

Exercise hemodynamics during long-term implantation of a left ventricular assist device in patients awaiting heart transplantation.

OBJECTIVES: The goal of this study was to assess patients with end-stage heart disease after implantation of a left ventricular assist device at rest and during exercise compatible with activities of daily life. BACKGROUND: Mechanical circulatory assistance with a left ventricular assist device is an accepted therapy for bridging patients with end-stage heart disease to heart transplantation and has been proposed for long-term implantation. METHODS: Three patients (aged 37, 42 and 57 years) with end-stage heart failure required implantation of a pneumatically driven, asynchronous Thermedics left ventricular assist device while awaiting heart transplantation. All were assessed 1 month later during graded supine bicycle exercise (maximal work load 100 to 150 W). Detailed central hemodynamics, including continuous pulmonary artery oxygen saturation and oxygen consumption measurements, were obtained. Two of the patients also underwent upright treadmill exercise with oxygen consumption measurements. RESULTS: During supine bicycle exercise, the heart rate increased from 93 +/- 37 beats/min (95% confidence interval: mean +/- t0.025 x SE) at rest to 119 +/- 54 beats/min and left ventricular assist device rate increased from 82 +/- 47 to 109 +/- 55 beats/min. Oxygen consumption increased from 3.0 +/- 0.9 to 8.7 +/- 2.9 ml oxygen/min per kg body weight. Cardiac output increased from 6.0 +/- 4.4 to 9.6 +/- 7.1 liters/min, yielding an average exercise factor of 8.5 +/- 7.7 and an exercise index of 0.83 +/- 0.61. The patients assessed during treadmill exercise achieved a maximal oxygen consumption of 14.3 and 16.7 ml of oxygen/min per kg. No thromboembolic or other complications attributable to left ventricular assist device implantation occurred during the duration of support. All patients survived orthotopic heart transplantation and are doing well. CONCLUSIONS: Significant work loads compatible with activities of daily life and adequate exercise hemodynamics were demonstrated by these patients while awaiting heart transplantation. Definitive conclusions regarding the use of this device must be viewed as preliminary because only three patients were involved in this study and the failure rate may be as high as 71% (95% confidence interval of left ventricular assist device success as a bridge to transplantation 29.3% to 100%). Final conclusions regarding the safety and efficacy of the left ventricular assist device as a possible long-term circulatory support device must await results of larger multicenter trials in progress.

Online bibliographic information: integration into an emerging IAIMS environment.

The Medical Library at Yale University has developed an online free-text database containing Current Contents citations. The database was designed to be integrated into an emerging campus-wide information environment. To this end Current Contents at Yale was designed with a user interface familiar to the Yale community, an alerting service based on electronic mail, and search expansion using the National Library of Medicine's Meta-1 metathesaurus.

Caffeine potentiates vasodilator-induced renin release.

Previous studies strongly suggest that adenosine receptors on juxtaglomerular cells function to restrain the secretion of renin induced by a variety of stimuli. The clinical significance of this is that caffeine, a widely consumed adenosine receptor antagonist, could augment renin release responses to diseases such as renovascular hypertension, liver cirrhosis and heart failure and to therapeutic maneuvers such as salt restriction, diuretics and vasodilators. Caffeine may be particularly troublesome in this regard because this methylxanthine has central nervous system effects and intracellular actions that also might contribute to the overall ability of caffeine to potentiate renin secretion. The purpose of this study was to document the effects of caffeine on renin release responses to a vasodilator and to investigate what mechanisms were responsible for any augmentation of vasodilator-induced renin secretion. Accordingly, we compared the effects of caffeine vs. 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; a xanthine that we documented in this study not to significantly enter the brain or penetrate cell membranes) on base-line and hydralazine-induced renin release in both normal and beta adrenoceptor-blocked (propranolol, 15 mg/kg) rats. Both xanthines (at a dose of 10 mg/kg plus 150 micrograms/min) attenuated adenosine-mediated hypotension and bradycardia, and DPSPX was at least as effective as caffeine in antagonizing peripheral adenosine receptors. Caffeine and DPSPX increased base-line plasma renin activity to a similar extent regardless of whether the animals were pretreated with propranolol. In rats with an intact beta adrenergic system, caffeine, but not DPSPX, increased the renin release response to low-dose hydralazine (1 mg/kg). Although both xanthines augmented the renin release response to high-dose hydralazine (10 mg/kg), caffeine was more efficacious in this regard. In beta adrenoceptor-blocked rats, neither caffeine nor DPSPX augmented the renin release response to low-dose hydralazine, whereas both xanthines equally potentiated the renin release response to high-dose hydralazine. These data demonstrate that caffeine increases base-line renin release primarily by blocking peripheral (most likely renal), cell-surface adenosine receptors; however, caffeine potentiates vasodilator-induced renin secretion in part by blocking peripheral (most likely renal), cell-surface adenosine receptors and in part by additional central nervous system and/or intracellular mechanism(s) that involve the beta adrenergic system.

Cardiac arrest after isoflurane anaesthesia in a patient with Duchenne's muscular dystrophy.

An 8-year-old boy known to have Duchenne's muscular dystrophy suffered a cardiac arrest 10 minutes after he regained consciousness after isoflurane anaesthesia for an orchidopexy procedure. Resuscitation was successful 2 hours after the start of external cardiac compression and after correction of hyperkalaemia and the administration of dantrolene. He later developed myoglobinuria elevated creatine kinase and a metabolic and respiratory acidosis. He demonstrated a delayed increase in rectal temperature.