Adam Pleister

Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts.

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. To date, the contribution of microRNAs (miRNAs) in DS has not been investigated. Bioinformatic analyses demonstrate that human chromosome 21 (Hsa21) harbors five miRNA genes; miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. MiRNA expression profiling, miRNA RT-PCR, and miRNA in situ hybridization experiments demonstrate that these miRNAs are overexpressed in fetal brain and heart specimens from individuals with DS when compared with age- and sex-matched controls. We hypothesize that trisomic 21 gene dosage overexpression of Hsa21-derived miRNAs results in the decreased expression of specific target proteins and contribute, in part, to features of the neuronal and cardiac DS phenotype. Importantly, Hsa21-derived miRNAs may provide novel therapeutic targets in the treatment of individuals with DS.

Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains.

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3′-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is underexpressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intra-ventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.

Sleep disordered breathing and post-discharge mortality in patients with acute heart failure

BACKGROUND Hospitalizations for heart failure are associated with a high post-discharge risk for mortality. Identification of modifiable predictors of post-discharge mortality during hospitalization may improve outcome. Sleep disordered breathing (SDB) is the most common co-morbidity in heart failure patients. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of patients hospitalized with acute heart failure (AHF) in a single academic heart hospital. Between January 2007 and December 2010, all patients hospitalized with AHF who have left ventricular ejection fraction (LVEF) ≤ 45% and were not already diagnosed with SDB were the target population. MAIN OUTCOMES AND MEASURES Patients underwent in-hospital attended polygraphy testing for SDB and were followed for a median of 3 years post-discharge. Mortality was recorded using national and state vital statistics databases. RESULTS During the study period, 1117 hospitalized AHF patients underwent successful sleep testing. Three hundred and forty-four patients (31%) had central sleep apnoea (CSA), 525(47%) patients had obstructive sleep apnoea (OSA), and 248 had no or minimal SDB (nmSDB). Of those, 1096 patients survived to discharge and were included in the mortality analysis. Central sleep apnoea was independently associated with mortality. The multivariable hazard ratio (HR) for time to death for CSA vs. nmSDB was 1.61 (95% CI: 1.1, 2.4, P = 0.02). Obstructive sleep apnoea was also independently associated with mortality with a multivariable HR vs. nmSDB of 1.53 (CI: 1.1, 2.2, P = 0.02). The Cox proportional hazards model adjusted for the following covariates: LVEF, age, BMI, sex, race, creatinine, diabetes, type of cardiomyopathy, coronary artery disease, chronic kidney disease, discharge systolic blood pressure <110, hypertension, discharge medications, initial length of stay, admission sodium, haemoglobin, and BUN. CONCLUSIONS This is the largest study to date to evaluate the effect of SDB on post-discharge mortality in patients with AHF. Newly diagnosed CSA and OSA during AHF hospitalization are independently associated with post-discharge mortality.

Physician reported perception in the treatment of high blood pressure does not correspond to practice

BackgroundHigh blood pressure is a significant health problem world-wide. Physician factors play a significant role in the suboptimal control of hypertension in the United States. We sought to better understand primary care physicians opinions regarding use of hypertension guidelines, patient and physician related barriers to treatment and physician treatment decision making in the management of hypertension as part of a first step in developing research tools and interventions designed to address these issues.MethodsAn IRB approved survey pertaining to physician opinion regarding the treatment of hypertension. Items consisted of questions regarding: 1) knowledge of hypertension treatment guidelines; 2) barriers to hypertension control (physician vs. patient); and 3) self-estimation of physician treatment of hypertension. Descriptive Statistics were used to describe results.ResultsAll physicians were board certified in family or general internal medicine (n = 28). Practices were located in urban (n = 12), suburban (n = 14) and inner city locations (n = 1). All physicians felt they did a good job of treating hypertension. Most physicians felt the biggest barrier to hypertension control was patient non-compliance. Half of physicians would fail to intensify treatment for hypertension when blood pressure was above recommended levels for all disease states studied (essential hypertension, heart disease, diabetes, and renal disease).ConclusionPhysician ability to assess personal performance in the treatment of hypertension and physician opinion that patient noncompliance is the greatest barrier to optimal hypertension control is contradictory to reported practice behavior. Optimal blood pressure control requires increased physician understanding on the evaluation and management of blood pressure. These data provide crucial formative data to enhance the content validity of physician education efforts currently underway to improve the treatment of blood pressure in the primary care setting.

Endothelial nitric oxide synthase uncoupling: A novel pathway in OSA induced vascular endothelial dysfunction

The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2(•-)) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor l-Nitroarginine-Methyl-Ester (l-NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2(•-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2(•-) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA.

Consequences of Obstructive Sleep Apnea: Cardiovascular Risk of Obstructive Sleep Apnea and Whether Continuous Positive Airway Pressure Reduces that Risk.

Obstructive sleep apnea (OSA) is present in up to 25% of otherwise healthy individuals. OSA is associated with intermittent hypoxia, oxidative stress, sympathetic activation, and an inflammatory response. These perturbations mediate the role of OSA as an independent and modifiable risk factor for cardiovascular disease (CVD). OSA can induce CVD or accelerate the progression of CVD into an end-stage disorder, including heart failure and stroke. Current clinical recommendations are based on existing clinical trial data and the clinical experience of our program; current and future clinical trials will help to optimize management of OSA in the setting of CVD.

Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure: Nesiritide Redux

Nesiritide, a synthetic drug form of human B-type natriuretic peptide, is approved for the early treatment of dyspnea in acute decompensated heart failure. Meta-analyses suggested a risk of worsening renal insufficiency and mortality with its use. Therefore, the Acute Study of Clinical Effectiveness in Decompensated Heart Failure (ASCEND-HF) was designed as a prospective, multicenter, double-blind, randomized trial to examine the use of nesiritide in this common, morbid, and often lethal clinical condition. Two coprimary end points, dyspnea and 30-day hospital readmission or death, were chosen to examine symptomatic response and objective outcomes, respectively. Preliminary reports from ASCEND-HF investigators suggest no significant improvement in symptoms or clinical outcomes, although no adverse effect on mortality or renal function was noted. We recommend the continued use of nesiritide in acute decompensated heart failure as an individualized case-based therapy to those patients who meet criteria for treatment and are expected to receive benefit from its use.

Therapeutic Lifestyle Changes for Cardiovascular Disease

Abstract Cardiovascular disease, including hypertension, coronary artery disease, and heart failure, is common in the general US population. The mainstay of treatment for this cohort is implementing therapeutic lifestyle changes (TLCs). Therapeutic lifestyle changes include a reduced-sodium diet, the Dietary Approaches to Stop Hypertension (DASH) diet, weight loss, moderation of alcohol consumption, and increased aerobic exercise. It is important to emphasize that exercise should be recommended to all patients, even for those who historically were told not do so, such as those with heart failure. When prescribing harmacotherapy, physical activity should be taken into account. Athletes competing at the top level warrant adherence to the restrictions of the World Anti-Doping Agency.

Identification and Treatment of Central Sleep Apnoea: Beyond SERVE-HF

Central sleep apnoea (CSA) occurs in a large proportion of HF patients. CSA has clear detrimental effects, resulting in intermittent hypoxia and sympathetic activation, and is associated with significant morbidity and mortality. Treatment options are limited following the results of a recent trial in which adaptive servo-ventilation resulted in an increase in cardiovascular mortality. Ongoing studies utilising other forms of positive airway pressure may provide additional insight into the results of this trial. A new neurostimulation therapy, phrenic nerve stimulation, has offered a new physiological approach to the treatment of CSA. This therapy has resulted in improvements in the severity of disease and quality of life.

Sleep-disordered breathing as a modifiable risk factor for cardiovascular disease

Cardiovascular disease (CVD) remains the leading cause of disease-related death in most developed countries. Sleep-disordered breathing (SDB), including both obstructive sleep apnea (OSA) and central sleep apnea (CSA), are increasing in overall prevalence and are often found in patients with established CVD. This review article will first discuss the most current medical literature regarding the clinical correlation between OSA and major CVDs, including systemic hypertension, cardiac arrhythmias, coronary artery disease, pulmonary hypertension, and stoke, as well as the current evidence of the impact of treatment of OSA on these conditions. Second, a focus on the correlation between sleep-disordered breathing and heart failure (HF) will be addressed, including existing evidence regarding the potential benefits of treatment of SDB on HF outcomes. Finally, we will address practical approaches to help guide clinical decision-making, in terms of which patients with CVD should be considered for treatment of co-existing SDB.