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.

Palpitations: Evaluation in the Primary Care Setting.

Palpitations are a common problem in the ambulatory primary care setting, and cardiac causes are the most concerning etiology. Psychiatric illness, adverse effects of prescription and over-the-counter medications, and substance use should also be considered. Distinguishing cardiac from noncardiac causes is important because of the risk of sudden death in those with an underlying cardiac etiology. A thorough history and physical examination, followed by targeted diagnostic testing, can distinguish cardiac conditions from other causes of palpitations. Persons with a history of cardiovascular disease, palpitations at work, or palpitations that affect sleep have an increased risk of a cardiac cause. A history of cardiac symptoms, a family history concerning for cardiac dysrhythmias, or abnormal physical examination or electrocardiography findings should prompt a more in-depth evaluation for heart disease. Ischemic symptoms may signal coronary heart disease and associated ventricular premature contractions that may warrant exercise stress testing. Exertional symptoms accompanied by elevated jugular venous pressure, rales, or lower extremity edema should raise concern for heart failure; imaging may be required to assess for functional and structural heart disease.

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.

Sleep Duration and Metabolic Syndrome. An Updated Dose-Risk Metaanalysis.

RATIONALE: Several studies have reported that both short and long sleep durations are associated with the metabolic syndrome, but whether a dose-response relationship exists is unclear. OBJECTIVES: We performed a metaanalysis to study the magnitude of the association between the different durations of sleep and metabolic syndrome. METHODS: We searched in the databases of PubMed, Web of Science, and Ovid (all Journals@Ovid) from inception to October 4, 2014 for cross-sectional studies where an association between metabolic syndrome and sleep duration was analyzed. MEASUREMENTS AND MAIN RESULTS: Eighteen studies with 75,657 participants were included. Daily sleep duration of 7 to 8 hours was used as the reference group. The odds ratio (OR) of having metabolic syndrome for short (<7 h) sleep was 1.23 (95% CI, 1.11-1.37; P < 0.001; I(2), 71%). The ORs for less than 5 hours, 5 to 6 hours, and 6 to 7 hours of sleep were 1.51 (95% CI, 1.10-2.08; P = 0.01), 1.28 (95% CI, 1.11-1.48; P < 0.001), and 1.16 (95% CI, 1.02-1.31; P = 0.02), respectively. The coefficient of sleep duration on log of ORs was -0.06 ± 0.02 (P = 0.02). The OR for long sleep duration was 1.13 (95% CI, 0.97-1.32; P = 0.10; I(2), 89%). CONCLUSIONS: A dose-response relationship exists between short sleep duration and metabolic syndrome. Those who report a sleep duration of less than 5 hours have a 1.5 higher odds of having metabolic syndrome. Our study does not support the notion that long sleep is associated with metabolic syndrome.

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.

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.

Echocardiography and heart failure: a glimpse of the right heart.

The catastrophic consequences for patients in the settings of certain clinical conditions such as acute right ventricular infarction or massive pulmonary embolism with right heart failure illustrate the essential role that the right ventricle plays in sustaining life. With the development of more sophisticated diagnostic imaging technologies at the end of the last century and the dawn of this century, the importance of the right ventricle has been clearly demonstrated. The continued and evolving nature of our understanding of the right ventricle was emphasized in 2006, when the National Heart, Blood, and Lung Institute formed a working group focused on developing a better understanding of the right ventricle in both healthy and disease states. The objective of this review paper is to examine the right ventricle structure and function and describe the role of echocardiography in the evaluation of the right ventricle and right heart failure. Special focus will be on echocardiographic images and major society guidelines.

Delocalization of Endogenous A-kinase Antagonizes Rap1-Rho-α2C-Adrenoceptor Signaling in Human Microvascular Smooth Muscle Cells.

The second messenger cyclic AMP (cAMP) plays a vital role in the physiology of the cardiovascular system, including vasodilation of large blood vessels. This study focused on cAMP signaling in peripheral blood vessels, specifically in human vascular smooth muscle (microVSM) cells explanted from skin punch biopsy arterioles (also known as resistance vessels) of healthy volunteers. Using these human microVSM we recently demonstrated cAMP activation of exchange protein activated by cAMP (Epac), the Ras-related small GTPase Rap1A, and RhoA-ROCK-F-actin signaling in human microVSM to increase expression and cell surface translocation of functional α2C-adrenoceptors (α2C-ARs) that mediate vasoconstriction. Protein-protein association with the actin-binding protein filamin-2 and phosphorylation of filamin-2 Ser2113 by cAMP-Rap1A-Rho-ROCK signaling were necessary for receptor translocation in these cells. Although cAMP activated A-kinase in these cells, these effects were independent of A-kinase, and suggested compartmentalized A-kinase local signaling facilitated by A-kinase anchoring proteins (AKAPs). In this study we globally disrupted A-kinase-AKAP interactions by the anchoring inhibitor decoy peptide Ht31 and examined the effect on α2C-AR expression, translocation, and function in quiescent microVSM treated with the adenylyl cyclase activator and cAMP elevating agent forskolin. The results show that Ht31, but not the control peptide Ht31-P, reduced forskolin-stimulated Ser133 phosphorylation of A-kinase substrate CREB, reduced α2C-AR mRNA levels, reduced cell surface translocated receptors, and attenuated agonist-triggered receptor functional responses. Together, the results suggest that compartmentalized cAMP signaling elicits a selective cellular response in microVSM, which may have relevance to arteriole physiological function and responses.

Circulating miRNAs: novel biomarkers of acute coronary syndrome?

Acute coronary syndrome refers to any group of clinical symptoms compatible with acute myocardial infarction (AMI). AMI is a major cause of death and disability worldwide with the greatest risk of death within the first hours of AMI onset. Therefore, delays in 'ruling in' AMI may increase morbidity and mortality due to the time lag in initiating therapy. Likewise, since the majority of patients presenting with acute chest pain do not have AMI, the rapid 'ruling out' of AMI in those patients would increase emergency department triage efficiency, decrease medical costs, and reduce morbidity and mortality. Thus, the identification of novel biomarkers that improve current strategies and/or accurately identify subjects who are at risk of developing acute and chronic manifestations of cardiovascular disease are desperately needed. This article discusses the potential of peripheral blood microRNAs as clinical biomarkers for the diagnosis and prognosis of cardiovascular diseases such as AMI.

Therapeutic lifestyle changes for cardiovascular disease.

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.

Outpatient approach to palpitations.

Palpitations are a common problem seen in family medicine; most are of cardiac origin, although an underlying psychiatric disorder, such as anxiety, is also common. Even if a psychiatric comorbidity does exist, it should not be assumed that palpitations are of a noncardiac etiology. Discerning cardiac from noncardiac causes is important given the potential risk of sudden death in those with an underlying cardiac etiology. History and physical examination followed by targeted diagnostic testing are necessary to distinguish a cardiac cause from other causes of palpitations. Standard 12-lead electrocardiography is an essential initial diagnostic test. Cardiac imaging is recommended if history, physical examination, or electrocardiography suggests structural heart disease. An intermittent event (loop) monitor is preferred for documenting cardiac arrhythmias, particularly when they occur infrequently. Ventricular and atrial premature contractions are common cardiac causes of palpitations; prognostic significance is dictated by the extent of underlying structural heart disease. Atrial fibrillation is the most common arrhythmia resulting in hospitalization; such patients are at increased risk of stroke. Patients with supraventricular tachycardia, long QT syndrome, ventricular tachycardia, or palpitations associated with syncope should be referred to a cardiologist.

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.

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.

When your patient's blood pressure won't come down.

Is your patient's persistent hypertension really resistant to treatment, or are other factors at work? Consider these 2 cases and let this algorithm help you decide.

Barriers to blood pressure control as reported by African American patients.

PURPOSE: To understand African American patients' opinions as to barriers to hypertension treatment. METHODS: Focus groups (n=3) were led by a trained African American moderator of African American patients with hypertension (n=26) who receive their care from a large primary care network. Discussions were transcribed verbatim. Information was displayed in a data matrix and analyzed for emerging themes. Descriptive statistics were used to enhance the content validity of lifestyle modification efforts planned as part of this ongoing research. RESULTS: Most participants were female (n=20), and the mean age was 49 years. All participants were at least high school graduates. Four major levels of influence emerged from data analysis: (1) the health care system, (2) the community, (3) the family, and (4) the individual. The most prevalent concerns about hypertension centered on sodium, diet, neighborhoods, mistrust, and denial. Of great concern was lack of provider trust and a fatalistic, hopeless mindset. To improve trust, our participants suggested developing a hypertension education program and providing patients with culturally specific materials. CONCLUSIONS: Culturally sensitive materials need to be designed and tested to improve blood pressure control. Community input regarding cultural issues is essential for designing effective and successful programs for reducing health disparities.

Sociology meets genetics: sociogenetic implications for future management of hypertension and heart failure.

Hypertension and heart failure contribute significantly to morbidity and mortality in the United States. Suboptimal control of these disease processes is multifactorial and involves poorly understood mechanisms affected by the environment (socioeconomic factors) and genetics (cell biology). Dietary sodium is an illustrative case. Although physicians intuitively accept that sodium affects renal and cardiovascular physiology, the complex overlay of genetics, environment, and culture is not practically addressed to make a meaningful difference in patient care. Optimal control of hypertension and heart failure will require a personalized care plan for each patient that includes lifestyle changes and carefully selected pharmacotherapy and also accounts for sociogenetic factors that affect each patient's life and thus his or her disease process. Physicians' cultural biases and perceptions also must be factored into this complex patient care equation.

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

BACKGROUND: High 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 physician's 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. METHODS: An 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. RESULTS: All 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). CONCLUSION: Physician 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.

Cardiomyopathy: an overview.

Cardiomyopathy is an anatomic and pathologic diagnosis associated with muscle or electrical dysfunction of the heart. Cardiomyopathies represent a heterogeneous group of diseases that often lead to progressive heart failure with significant morbidity and mortality. Cardiomyopathies may be primary (i.e., genetic, mixed, or acquired) or secondary (e.g., infiltrative, toxic, inflammatory). Major types include dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although cardiomyopathy is asymptomatic in the early stages, symptoms are the same as those characteristically seen in any type of heart failure and may include shortness of breath, fatigue, cough, orthopnea, paroxysmal nocturnal dyspnea, and edema. Diagnostic studies include B-type natriuretic peptide levels, baseline serum chemistries, electrocardiography, and echocardiography. Treatment is targeted at relieving the symptoms of heart failure and reducing rates of heart failure-related hospitalization and mortality. Treatment options include pharmacotherapy, implantable cardioverter-defibrillators, cardiac resynchronization therapy, and heart transplantation. Recommended lifestyle changes include restricting alcohol consumption, losing weight, exercising, quitting smoking, and eating a low-sodium diet.

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.