End-organ Effects Research Articles

Severe intraoperative hypertension after induction of anesthesia in a child with a neuroblastoma

Neuroblastomas are the most common, non-central nervous system tumor of childhood. Similar to pheochromocytomas, they are derived from neural crest cells and therefore retain the potential to synthesize catecholamines. Unlike pheochromocytomas, however, perioperative issues related to blood pressure instability with hypertension are uncommon. We report details of a 3-year-old child with a neuroblastoma who developed severe hypertension and end-organ effects after induction of anesthesia. The association of such problems with neuroblastoma is reviewed and options for perioperative care presented.

Dry Gangrene Of The Glans Penis In A Patient With Bilateral Foot Ulcers And Severe Vascular Disease: A Case Report

Orthopaedic surgeons, particular foot and ankle surgeons are frequently asked to assist with the treatment of patients with lower extremity ulcerations and infections related to diabetes and/or vascular disease. The case report presents the history and clinical images of a patient with diabetes and multiple medical co-morbidities who presented with bilateral lower extremity ulcerations and dry gangrene of the glans penis. This case is presented because it is a striking example of the end-organ effects of diabetes and associated vascular disease.

Mineralocorticoid Receptor-Associated Hypertension and Target Organ Damage: Clinical Relevance for Resistant Hypertension in End Stage Renal Disease

Mineralocorticoid receptor (MR) blockade has proven efficacy in the treatment of hypertension and in improving morbidity and mortality in patients with heart failure. The potential importance of mineralocorticoid receptor blockade has grown recently amid the observation that angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers do not effectively reduce aldosterone levels in all patients over the long term. To date, research on the role of MR blockade has primarily focused on resistant hypertension, decreasing proteinuria, and potentially preventing disease progression in early stages of chronic kidney disease (CKD). Given the prevalence of co-morbid resistant hypertension and cardiovascular disease in patients with end-stage renal disease (ESRD), however, interest in the role of MR blockade in this patient population has arisen. In this paper, we review the current evidence for using MR blockade in mild-tomoderate and resistant hypertension in patients with normal renal function, CKD, and ESRD. We discuss recent animal and human studies on the role of aldosterone in mediating hypertension as well as vascular and tissue damage. We then review clinical studies on the use of MR blockade in ameliorating aldosterone’s deleterious end organ effects and its applicability to patients with ESRD. Finally, we summarize the evidence to date supporting the safety of MR blockade in patients with ESRD.

Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs

Cardiac stress responses are driven by an evolutionarily conserved gene expression program comprising dozens of microRNAs and hundreds of mRNAs. Functionalities of different individual microRNAs are being studied, but the overall purpose of interactions between stress-regulated microRNAs and mRNAs and potentially distinct roles for microRNA-mediated epigenetic and conventional transcriptional genetic reprogramming of the stressed heart are unknown. Here we used deep sequencing to interrogate microRNA and mRNA regulation in pressure-overloaded mouse hearts, and performed a genome-wide examination of microRNA-mRNA interactions during early cardiac hypertrophy. Based on abundance and regulatory patterns, cardiac microRNAs were categorized as constitutively expressed housekeeping, regulated homeostatic, or dynamic early stress-responsive microRNAs. Regulation of 62 stress-responsive cardiac microRNAs directly affected levels of only 66 mRNAs, but the global impact of microRNA-mediated epigenetic regulation was amplified by preferential targeting of mRNAs encoding transcription factors, kinases, and phosphatases exerting amplified secondary effects. Thus, an emergent cooperative property of stress-regulated microRNAs is orchestration of transcriptional and posttranslational events that help determine the stress-reactive cardiac phenotype. This global functionality explains how large end-organ effects can be induced through modest individual changes in target mRNA and protein content by microRNAs that sense and respond dynamically to a changing physiological milieu.

17IN - Pharmacogenetics /Genomics (PGX) to Optimize Endocrine Therapy

ABSTRACT Endocrine therapy of breast cancer is associated with substantial variability between patients in terms of efficacy, adverse events and end organ effects indicating genetic variability. This discussion will consider the host (germline) genome and consider SERMs and 3rd generation AIs. In of terms of single gene studies, most of the work has been done with CYP2D6 and tamoxifen efficacy (first reported by our group in 2005) but the results have been mixed, related (in this author's opinion) to a series of flawed retrospective studies. Additional studies focusing on tamoxifen have examined polymorphisms in phase II (conjugating) enzymes (UGTs, SULTs), ESR1 and ESR2, but results remain preliminary. Our group conducted the largest PGx GWAS to date in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2 and identified SNPs associated with development of breast cancer and SNP-dependent mechanisms underlying SERM and estrogen-dependent regulation of BRCA1 expression. Considering AIs, substantial research has occurred relating to the aromatase gene CYP19. Our group has conducted GWAS in postmenopausal women with baseline hormone levels as the phenotype and identified SNPs related to estradiol levels, that achieved genome-wide significance, with one SNP creating an estrogen response element (ERE), and regulation by these SNPs of estrogen-dependent TSPYL5 induction and CYP19 adipose promotors induction. We also identified a genome-wide significant non-synonymous SNP in SLCO1B1 associated with estrone-conjugate levels. We have completed a GWAS in women receiving AIs with musculoskeletal adverse events (MS-AE) as the phenotype and identified a SNP that created an ERE, was associated with estrogen-dependent TCL1A expression, which in turn altered interleukin (IL) 17 receptor (R) A expression, IL-17, IL-12, IL-RB2, and IL-1R2 expression, as well as NF-κB transcriptional activity. These finding provide a pharmacological explanation for MS-AE in women treated with AIs. To date, PGx studies have not produced changes in clinical practice of endocrine therapy for breast cancer. In several instances they have served as discovery tools that provided direction for research that has led to new knowledge of the biology underlying endocrine therapy. Disclosure The author has declared no conflicts of interest.

Impact of Male Hormonal Contraception on Prostate Androgens and Androgen Action in Healthy Men: A Randomized, Controlled Trial

Male hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health. The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action. This was a single-blind, randomized, placebo-controlled study. The study was conducted at an academic medical center. 32 healthy men aged 25-55 yr participated in the study. Interventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10. Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured. Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm. MHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed.

Hyperthermia and Multiorgan Failure After Abuse of “Bath Salts” Containing 3,4-Methylenedioxypyrovalerone

"Bath salts" are being increasingly used as drugs of abuse. These products have been found to contain a variety of compounds, including 3,4-methylenedioxypyrovalerone (MDPV). We present a case of a 25-year-old man who injected bath salts and acutely developed severe agitation, hyperthermia, and tachycardia. Despite aggressive early medical management, including dialysis, he progressed to multiorgan system failure, although he ultimately recovered after a prolonged hospital course. The only chemical substance detected on comprehensive toxicologic testing was MDPV, a synthetic cathinone analogue. According to our case, MDPV abuse may result in adverse multisystem organ effects, including rhabdomyolysis, cardiac injury, hepatic injury, and renal failure. It is unknown whether these end-organ effects were due to direct cellular toxicity induced by MDPV or a result of the patient's marked agitation and hyperthermia. Acute management should focus on the rapid identification of organ injury and appropriate supportive care.

Glycemic memory

The mistake of predicting the future is perhaps not tending to repressed or past memories. Hamlet's 17th-Century soliloquy 'the heartache and the thousand natural shocks, that flesh is heir to', (3.1. 7-8) is a tale that looks beyond the present by linking the past with the future. The present article examines the resurgence in the field to understand gene-regulating epigenetic changes conferring glycemic memory. Chromatin modifications are critical in regulating genome structure and function and despite the significant advances of recent years in identifying the enzymes-mediating chemical changes to histone tails and the DNA template, the precise regulation of gene expression remains incomplete in models of health and diabetic complications. Dispelling the myth that all genomes are driven and respond equally, experimental research is now uncovering the function of enzymes conferring chromatin modifications. Whatever the role of the epigenome, showing its involvement in glycemic signaling is the first step to new strategies and targets to develop therapies that prevent, retard or reverse the long-term deleterious end-organ effects of chronic, intermittent and prior hyperglycemia.

In Response

It was not our intention to discuss the details of coronary microvascular control, because the focus of our reviews was on the effects of receptors throughout the circulation.1,2 Dr. Crystal3 and others4 have shown that to variable degrees, the myocardium is capable of regulating oxygen supply in response to changes in demand, an ability not unique to the myocardium.5 Like all organs capable of autoregulation, when demand is excessive or supply too scarce, autoregulation fails. This phenomenon is the primary interest of our manuscripts, and this inability to autoregulate ad infinitum has been shown in multiple organ systems. Our allusion to Dr. Antonopoulos's manuscript6 was for the sake of completeness; we acknowledged the difficulty of interpreting this interesting manuscript and therefore supported its conclusions with 3 additional studies. Alpha-adrenergic agonists have differential end-organ effects. Few organs can autoregulate as efficiently as the heart, which likely explains its relative resistance to changes in myocardial flow following α-adrenergic stimulation. As Dr. Crystal notes, when myocardial work is increased by systemic arteriolar constriction and a marked increase in blood pressure, the local autoregulation in the coronary microvasculature of healthy hearts can counterbalance increased α-adrenergic stimulation in these vessels, as demonstrated by his studies7 and others. We agree that the work of Dr. Crystal and others suggests potential mechanisms for this observation; whether this remains clinically significant in the face of significantly increased demand is unknown. However, various clinical studies suggest that in patients8 in whom coronary circulation is diseased at the level of the large or small vessels (e.g., mechanical or biochemical disruption of endothelial function; inflammatory activation within the vascular smooth muscle), the microcirculatory control may become imbalanced. Consequently, the statement “the myocardium is not at risk when phenylephrine is used to treat hypotension in patients with adequate cardiac function and coronary vasodilator reserve” must be viewed in the context of experimental work or the more ambiguous clinical setting. Edward C. Nemergut, MD Carl Lynch III, MD, PhD H. Thiele, MD Departments of Anesthesiology and Neurological Surgery University of Virginia Health System Charlottesville, VA Department of Anesthesiology Duke University Hospital Durham, NC [email protected]

CMR in inflammatory vasculitis.

Vasculitis, the inflammation of blood vessels, can produce devastating complications such as blindness, renal failure, aortic rupture and heart failure through a variety of end-organ effects. Noninvasive imaging with cardiovascular magnetic resonance (CMR) has contributed to improved and earlier diagnosis. CMR may also be used in serial evaluation of such patients as a marker of treatment response and as an indicator of subsequent complications. Unique strengths of CMR favoring its use in such conditions are its abilities to noninvasively visualize both lumen and vessel wall with high resolution. This case-based review focuses on the large- and medium-vessel vasculitides where MR angiography has the greatest utility. Because of increasing recognition of cardiac involvement in small-vessel vasculitides, this review also presents evidence supporting greater consideration of CMR to detect and quantify myocardial microvascular disease. CMR’s complementary role amidst traditional clinical, serological and other diagnostic techniques in personalized care for patients with vasculitis is emphasized. Specifically, the CMR laboratory can address questions related to extent and severity of vascular involvement. As ongoing basic and translational studies better elucidate poorly-defined underlying molecular mechanisms, this review concludes with a discussion of potential directions for the development of more targeted imaging approaches.

Ten Year Survivors of Multiple Myeloma Demonstrate a Differential Expression of Immunological Biomarkers Including a High Incidence of Cytotoxic T-Cell Clones Which Have Not Acquired Myeloma-Associated Anergy,

Abstract 3924▪▪This icon denotes a clinically relevant abstractPrior to the introduction of novel therapies for patients with multiple myeloma (MM) few patients survived for more than 10 years. Several reports have suggested that 10 year survival is associated with a younger age at diagnosis and the duration of exposure to effective agents. Although the number of patients surviving 10 years is increasing, there have been no significant reports of immunological biomarkers in these patients. This is especially true in those for whom the prolonged survival has occurred without novel drugs. Previous studies have shown that the presence of expanded peripheral blood CD8 T-cell clones in MM patients is associated with a better prognosis; raising the possibility that these T-cells, confirmed as clones by TCR sequencing, mediate an anti-tumor effect. However microarray gene set enrichment analysis and proliferation tracking studies demonstrated that these cells are in an anergic state. In addition, there is evidence that Tregs inhibit and Th17 cells enhance autologous immune response in malignancy and that an imbalance in MM may impair disease control. Slan-DCs are a subset of myeloid dendritic cells and are of interest in MM because of their ability to stimulate cytotoxic T-cell responses and reverse anergy in tumor infiltrating lymphocytes.We have investigated the immune mechanisms of disease control which may contribute to long-term survival by analyzing Tregs, Th17 cells, Slan-DCs and the incidence and relative degree of anergy of T-cell clones in all current >10 year survivors.Peripheral blood samples were analyzed for the presence of CD3+ T-cell receptor Vβ restricted T-cell clones (BetaMark Kit), the number of CD3+CD4+CD25h+CD127- Tregs, CD4+IL-17+ Th17 cells and CD16+CD14low M-DC8+ Slan-DCs. Proliferation of T-cells was analyzed using CFSE tracked 4 day cultures stimulated with anti-CD3 and anti-CD28 beads. Results were compared with local data collected from 2 large MM cohorts and age-matched controls.Of 26 patients who had survived for >10 years, 22 were available for testing. At diagnosis the median age was 59y (median=57y in comparison cohort); 54% were female; median β2M was 2.2mg/L (range 1.1–7.3); 92% were ISS I; 73% of paraproteins were IgG, 23% IgA and 4% light chain only. 73% had end-organ effects with; 65% bone disease; 15% anemia and 8% renal impairment. 58% had received cytotoxic chemotherapy; 27% novel agents; 38% autologous transplants; 8% allogeneic transplants and 31% were untreated. Expanded T-cell clones were documented in all (100%) of the 10 year survivors, a significant increase compared with 54% (n=144) and 48% (n=120) in the previous MM cohorts (χ2=43.6;p<0.001). Tregs accounted for 5.7% of CD4+ cells in the 10 year survivors which was significantly less than the 8.9% in the all-MM cohort (t=3.1; p< 0.005) but similar to 6.5% in age-matched controls. Proportions of Th17 cells were significantly greater in the 10 year survivor group (3.3% of CD4+ cells) than in the previous MM cohort (0.72%; U= 78; p< 0.005). Both absolute and percent mean Slan-DC numbers were significantly higher in the 10 year survivors than the all-MM cohort (0.17% vs 0.1%; t=2.5, p<0.02). Proliferation of clonal T cells was markedly greater in the 10-year survivors than the all-MM cohort (median 84% and 4% respectively; p<0.001) suggesting that they are more responsive.Analysis of immunological biomarkers in >10 year survivors of MM was compared to a large MM cohort and demonstrated a statistically significant decrease in T-regs with an increase in Th17 cells, absolute Slan-DCs and incidence of T-cell clones. These T-cell clones are more responsive than those in an all-MM cohort suggesting they have acquired less MM-associated anergy. This demonstrates that immunological mechanisms are active in long term disease control in MM and suggests that overcoming anergy of cytotoxic T-cells should be a focus of future studies. Disclosures:No relevant conflicts of interest to declare.

Carotid Intima-Media Thickness, Electrocardiographic Left Ventricular Hypertrophy, and Incidence of Intracerebral Hemorrhage

Carotid intima-media thickness and electrocardiographic left ventricular hypertrophy are 2 subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased intima-media thickness and electrocardiographic left ventricular hypertrophy also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid intima-media thickness and the presence of electrocardiographic left ventricular hypertrophy would be independently associated with increased ICH incidence. Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid intima-media thickness, carotid plaque, and electrocardiographic left ventricular hypertrophy. Over a median of 18 years of follow-up, 162 incident ICH events occurred. After adjustment for other ICH risk factors, carotid intima-media thickness was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific Quartile 1, elevated 1.6- to 2.6-fold in Quartiles 2 to 3, and elevated 2.5 to 3.7-fold in Quartile 4 (P<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI, 1.1-3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI, 0.76-2.0) greater ICH risk in ARIC. Electrocardiographic left ventricular hypertrophy carried a hazard ratio of ICH of 1.7 (95% CI, 0.77-3.7) in CHS and 2.8 (95% CI, 1.2-6.4) in ARIC. Our data suggest that people with carotid atherosclerosis and possibly left ventricular hypertrophy are at increased risk not only of ischemic stroke, but also of ICH.

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Systemic administration of fluorogold for anatomical pre‐labeling of autonomic and motor neurons in the rat spinal cord compromises urodynamic recordings in acute but not long‐term studies

The use of anatomical tracer injections into peripheral tissues for retrograde labeling of spinal cord neurons may compromise physiological experiments in combined functional and morphological studies. We investigated whether a systemic injection of a retrogradely transported tracer, fluorogold (FG), may provide an alternative to direct injections into end organs for combined anatomical and physiological studies of the lower urinary tract. Urodynamic studies including cystometrogram recordings and external urethral sphincter electromyography were used as functional outcome measures. Pre-labeling of spinal cord neurons by intraperitoneal (i.p.) administration of FG resulted in a transient decrease in voiding efficiency, increase in resting pressure as well as increase in bladder size and weight at 5-7 days after the tracer administration. In contrast, there were no urodynamic or end-organ effects detected at 6-8 weeks after the i.p. injection of FG. We suggest that pre-labeling of spinal autonomic and motor neurons using i.p. administration of FG may be a useful tool when combining anatomical and functional outcome measures in long-term but not acute studies.

Unusual presentation of hemochromatosis as isolated metacarpophalangeal joint osteoarthritis: a case report.

Hemochromatosis, North America's most prevalent genetic disorder, tends to present with an insidious onset and subtle, yet characteristic findings. Patients tend to present with both constitutional symptoms and end-organ effects. Clinical criteria such as history, physical examination, imaging criteria with focused radiologic constellations, and laboratory findings were used for diagnosis. We report the case of a man who lacked classic systemic symptoms, but instead presented with isolated metacarpophalangeal joint disease and characteristic radiologic findings. The diagnosis was confirmed by serum iron studies and subsequent genetic work-up. A high index of clinical suspicion is required to diagnose early disease; better prognostic responses are expected with treatment of less severe disease. Hand surgeons should be aware of the characteristic findings for this rare presentation so proper treatment can be initiated early.

Potential Benefits of Aliskiren Beyond Blood Pressure Reduction

There is now clear evidence that reducing blood pressure (BP) with a broad range of agents, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, improves cardiovascular and renal outcomes. There is also evidence suggesting that these drugs have beneficial effects that are independent of BP lowering. Aliskiren is a direct renin inhibitor that interrupts the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step. Unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aliskiren produces a sustained reduction in plasma renin activity and reduces plasma levels of angiotensin II and aldosterone. Preclinical data and clinical trials in high-risk patients using surrogate markers increasingly suggest that aliskiren can reduce the progression of end-organ damage beyond that afforded by BP control. With its unique mechanism of action, combining aliskiren with another RAAS-blocking agent that has a different mechanism of action may provide more comprehensive blockade of the RAAS, potentially conferring additional clinical benefits. Evaluation of these end-organ effects in humans is underway in clinical trials designed to assess the effects of aliskiren alone and in combination with other antihypertensive agents on cardiovascular and renal outcomes.

Eplerenone suppresses aldosterone/ salt-induced expression of NOX-4

Salt-induced hypertension in the Dahl rat is associated with increases in angiotensin II, aldosterone, free radical generation and endothelial dysfunction. However, little is known about the specific mechanism(s) associated with the end-organ damage effects of aldosterone. We hypothesised that eplerenone reduces kidney damage by blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Dahl salt-sensitive rats fed either a low-salt (LS) or high-salt (HS) diet were treated with aldosterone in the presence of eplerenone or apocynin. Indirect blood pressure was measured prior to start of diet and weekly thereafter. Levels of plasma nitric oxide (NO) and urinary 8-isoprostane were measured following treatment. Protein levels of selected subunits of NADPH were assessed by western blot. Eplerenone and apocynin inhibited the rise in blood pressure induced by HS and/or aldosterone. This observation was accompanied with a parallel change in kidney protein levels of NADPH oxidase 4 (NOX-4) and p22phox. Aldosterone and high salt were associated with lower NO levels and greater renal oxidative stress. NADPH oxidase is associated with the vascular and renal remodelling observed in high dietary salt intake. Aldosterone-induced expression of NOX-4 plays a pivotal role in the end-organ damage effect of aldosterone, as eplerenone tended to reduce kidney damage and inhibit NOX expression.

One-lung ventilation and arterial oxygenation

Hypoxemia during one-lung ventilation (OLV) has become less common; however, it may still occur in about 10% of cases. We review recent developments which may affect the incidence and treatment of hypoxemia during OLV. Changes in surgical techniques are affecting oxygenation during OLV. The increased use of the supine position may adversely affect the prevalence of hypoxemia, whereas the increased application of thoracoscopic techniques is limiting the treatment options. Treatment options such as global or selective recruitment maneuvers and drug effects of dexmedetomidine and epoprostenol on arterial oxygenation during OLV are discussed. Capnometry prior to, or early during OLV, may in fact be able to predict the degree of hypoxemia during OLV. Persistent controversies surrounding the effect of epidural anesthesia, ventilatory modalities and gravity are reviewed. Interesting concepts have emerged from case reports and small studies on the treatment and prediction of hypoxemia during OLV. Definitive studies on the most effective ventilatory mode remain elusive. End-organ effects of OLV are an exciting new concept that may shape clinical practice and research going forward.

The influence of sacral nerve stimulation on anorectal dysfunction

Sacral nerve stimulation (SNS) has become an established option in the management of defaecatory disorders. There are many data on the end-organ effects of SNS, but limited consensus on its mechanism of action. The objective of this review was to determine the effect of sacral nerve stimulation (SNS) on anorectal function. Systematic literature review of the effect of sacral nerve stimulation (SNS) on anorectal function. There was significant heterogeneity of data pertaining to the effects of SNS on anorectal function, with no consistent change in physiological measures identified. Most data supported a mixed mechanism of action on anal motor and rectal sensory functioning. To date, conflicting data exist on the mechanism of action of SNS as determined by end-organ changes in anorectal physiology. Nevertheless, the data as they stand best support a mixed mechanism of action on anal motor and rectal sensory functions.

Safety and Efficacy of Dronedarone in the Treatment of Atrial Fibrillation/Flutter

Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, shortening its half-life. Dronedarone has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF.