Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support.

BACKGROUND: Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). METHODS AND RESULTS: Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs. CONCLUSIONS: The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Ataxia telangiectasia mutated influences cytochrome c oxidase activity.

Cells lacking ataxia telangiectasia mutated (ATM) have impaired mitochondrial function. Furthermore, mammalian cells lacking ATM have increased levels of reactive oxygen species (ROS) as well as mitochondrial DNA (mtDNA) deletions in the region encoding for cytochrome c oxidase (COX). We hypothesized that ATM specifically influences COX activity in skeletal muscle. COX activity was ∼40% lower in tibialis anterior from ATM-deficient mice than for wild-type mice (P < 0.01, n = 9/group). However, there were no ATM-related differences in activity of succinate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, mitochondrial glycerol 3-phosphate dehydrogenase, or complex III. Incubation of wild-type extensor digitorum longus muscles for 1h with the ATM inhibitor KU55933 caused a ∼50% reduction (P<0.05, n = 5/group) in COX activity compared to muscles incubated with vehicle alone. Among the control muscles and muscles treated with the ATM inhibitor, COX activity was correlated (r = 0.61, P<0.05) with activity of glucose 6-phosphate dehydrogenase, a key determinant of antioxidant defense through production of NADPH. Overall, the findings suggest that ATM has a protective role for COX activity.

Cardiac risk of noncardiac surgery.

Major perioperative cardiac events are estimated to complicate between 1.4% and 3.9% of surgeries. Because most surgeries are elective, there is the opportunity to implement strategies to reduce this risk. Accurate identification of patients at risk for such events will allow patients to be better informed about the benefit-to-risk ratio of procedures, and guide allotment of limited clinical resources, utilization of preventive interventions, and areas of future research. This review focuses on important features of the initial pre-operative clinical risk assessment, indications for diagnostic testing to quantify cardiac risk, and the methods and indications for pre-emptive therapies.

Acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection.

Acute type B aortic dissection comprises approximately one-third of all aortic dissection cases. Although this catastrophic cardiovascular condition was first described in the medical literature over two centuries ago, data on the optimal diagnostic and treatment modalities for type B dissection was slow to evolve throughout the latter half of the twentieth century, even as newer diagnostic techniques and management strategies became commonplace. To further elucidate contemporary practice patterns and outcomes of aortic dissection, the International Registry of Acute Aortic Dissection (IRAD) was established in 1996. Over the past two decades, IRAD publications have steadily increased our knowledge and understanding about aortic dissection. Specifically in recent years, analyses of IRAD data have gone beyond simply characterizing the patient with acute type B aortic dissection and have attempted to identify the means by which the outcome of such a patient could be improved. Thus, we present herein three areas in which IRAD data has recently advanced our understanding of acute type B aortic dissection: temporal classification especially for the subacute time period, risk stratification for identifying complicated cases, and thoracic endovascular aortic repair (TEVAR).

Ezetimibe in combination with a statin does not reduce all-cause mortality.

BACKGROUND: Although the ezetimibe-statin combination has been shown to reduce LDL cholesterol by 12% compared to a statin alone, its effect on hard clinical endpoints such as mortality is less certain. Prior trials evaluated this combination in highly select population groups, but impact on all- cause mortality in the general population has not been reported. METHODS: A total of 3,827 subjects who were prescribed either a statin (group 1) or the combination of statin with ezetimibe (group 2) between January 1st, 2005 and January 1st, 2008 were studied. Socio-demographic and clinical variables and mortality records were analyzed. Univariate and stepwise multivariate logistic regression analysis was performed to identify the impact of ezetimibe on all-cause mortality, controlling for patient characteristics, selected cardiovascular diseases and risk factors, and medications. RESULTS: Group 1 (n = 2,909), and group 2 (n = 918) were similar in regards to most demographic variables, 152 patients died from any cause during the study period. There was no difference in all cause mortality between the groups. Hypertension, higher HDL-C and omega-3 fatty acid use were associated with ezetimibe use in this cohort of patients and were considered as covariates in the analysis. Patients on the drug combination did not experience lower mortality after controlling for covariates and other significant risk factors. CONCLUSIONS: No significant mortality benefit was found with the use of ezetimibe in combination with a statin over use of a statin alone. Omega-3 fatty acid use and higher HDL-C demonstrated a substantial survival benefit.

Estimating the adoption of transcatheter aortic valve replacement by US interventional cardiologists and clinical trialists.

BACKGROUND: Despite extensive attention dedicated to transcatheter aortic valve replacement (TAVR) in both the medical literature and lay press, little is known about the anticipated utilization of TAVR by the US cardiology community. HYPOTHESIS: TAVR use is likely to outstrip its initial clinical indications. METHODS: Four days after approval of the first TAVR device in November 2011 by the US Food and Drug Administration, we emailed an online questionnaire to 201 authors of major TAVR clinical trials (trialists) and 461 recent members of an interventional cardiology professional society (clinicians). Responses were compared using χ(2) , t tests, and analysis of variance. RESULTS: Of 205 surveys received (response rate 31%; 114 clinicians, 91 trialists), the majority of respondents were interventionalists (86%) working in academic practices (72%). Although most physicians anticipated referring <25% of their patients with severe aortic stenosis for TAVR, 68% believed that TAVR is equally efficacious as open-heart surgery, and 11% believed that moderate-surgical risk patients should also be considered for TAVR. More clinicians (98%) than trialists (81%) expected to routinely refer patients for TAVR (P < 0.001). Furthermore, the clinicians were anticipating less operator training and lower annual volume requirements for performing TAVR, when compared with the trialists (P ≤ 0.001). CONCLUSIONS: Our findings suggest optimism for TAVR acceptance in the United States., with more conservative expectations regarding training, procedural volume requirements, and anticipated referral patterns among TAVR trialists than clinical interventionalists.

How to build an integrated biobank: the Washington University Translational Cardiovascular Biobank & Repository experience.

Translational studies that assess and extend observations made in animal models of human pathology to elucidate relevant and important determinants of human diseases require the availability of viable human tissue samples. However, there are a number of technical and practical obstacles that must be overcome in order to perform cellular and electrophysiological studies of the human heart. In addition, changing paradigms of how diseases are diagnosed, studied and treated require increasingly complex integration of rigorous disease phenotyping, tissue characterization and detailed delineation of a multitude of "_omics". Realizing the need for quality-controlled human cardiovascular tissue acquisition, annotation, biobanking and distribution, we established the Translational Cardiovascular Biobank & Repository at Washington University School of Medicine. Several critical details are essential for the success of cardiovascular biobanking including coordinated, trained and dedicated staff members; adequate, nonrestrictive informed consent protocols; and fully integrated clinical data management applications for annotating, tracking and sharing of tissue and data resources. Labor and capital investments into growing biobanking resources will facilitate collaborative efforts aimed at limiting morbidity and mortality due to heart disease and improving overall cardiovascular health.

Number of medications is associated with outcomes in the elderly patient with metabolic syndrome.

BACKGROUND: The diagnosis of metabolic syndrome indicates a clustering of metabolic imbalances which in sum have been recognized as a major predictor of cardiovascular and all-cause mortality. The aim of this study was to assess the level of under-pharmacy and poly-pharmacy and its prognostic impact in elderly patients with metabolic syndrome. METHODS: Retrospective chart-review at a tertiary medical center, of 324 patients greater than 65 years of age who met the International Diabetes Foundation criteria for metabolic syndrome diagnosis [Body Mass Index (BMI) > 30 kg/m(2), diagnosis of type 2 diabetes, hypertension, and dyslipidemia]. RESULTS: There were 60 (18.5%) patients in the low (≤ 5) medication burden group, 159 (49.1%) in the medium (> 5 and ≤ 10) medication burden group, and 105 (32.4%) in the high (> 10) medication burden group. At baseline, the groups differed only by systolic blood pressure. At two years follow-up, the medium group had significantly better improvement in high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), HbA1c, and systolic blood pressure compared to the low medication burden group and significantly better improvement in triglycerides, Haemoglobin A1c (HbA1c) and systolic blood pressure compared to the high medication group. Decrease in HDL-C was the only variable associated with strokes. High medication burden predicted hospitalization burden. The number of anti-hypertensives, history of tobacco use, low and high medication burdens and decrease in HDL-C were all associated with death. CONCLUSIONS: Both poly-pharmacy and under-pharmacy are associated with a decreased therapeutic benefit among patients with metabolic syndrome in terms of important laboratory measurements as well as clinical outcomes such as myocardial infarctions, hospitalization, and death.