Complex Cardiovascular Disease Research Articles

The Paradigm of Systems Biology Applied to Cardiovascular Diseases

Based on individual analyses of the functional components of an organism, the Oslerian method shows signs of depletion when attempting to explain the pathophysiology of complex syndromes such as cancer and cardiovascular diseases. This is why it is gradually being supplanted by a new paradigm: the methodology of biological systems. This new model strives to integrate knowledge in different modern research areas with the omics sciences and bioinformatics, in order to develop biological networks leading to a better understanding of these complex syndromes. The purpose of this review is to introduce clinical cardiologists and cardiovascular researchers a new tool called systems biology, showing how it integrates data from the omics sciences and its contribution to a new approach to cardiovascular disease. To date, a search of the Medline database has been conducted with the following key words in Portuguese and English: “biologia de sistemas”, “insuficiencia cardiaca”, “sindrome metabolica” e “arritmias cardiacas”; “systems biology”, “heart failure”, “metabolic syndrome” and “cardiac arrhythmias”. This led to the conclusion that systems biology must be used to an increasing extent for a better understanding of complex cardiovascular diseases such as metabolic syndrome, atherosclerosis, hypertension, heart failure and cardiac arrhythmias. Cardiologists, cardiovascular researchers, other healthcare practitioners and basic researchers in other fields of knowledge will build up closer links in a quest to identify health and disease network models that are now called network medicine.

Utility of feed-and-sleep cardiovascular magnetic resonance in young infants with complex cardiovascular disease.

Utilization of cardiovascular magnetic resonance (CMR) is limited in young children because of the need for sedation or general anesthesia (GA). It has been previously shown that CMR can be performed without sedation or GA in young infants who are prone to fall asleep after being fed and swaddled. The purpose of this study was to prospectively prove the feasibility of the feed-and-sleep CMR technique in larger cohorts in the two institutions where the technique was initially developed. This was a prospective dual-center cohort study over a two-year period. All infants younger than 6 months old with complex congenital cardiovascular anomaly who required CMR were recruited for this study. The exclusion criteria included mechanical ventilation, oxygen dependence, feeding difficulties, and any contraindication to CMR. The feed-and-sleep study was performed by fasting the infant for a period of 4 h prior to the scan, placing the infant in a vacuum immobilizer, and feeding the infant just prior to the CMR. The CMR sequences were prioritized to target the area of most importance first. A study was considered complete and diagnostic if the clinical question was answered. A total of 60 infants (39 from center A and 21 from center B) were recruited for this study, 32 male and 28 female, ages ranging from 1 to 177 days (50 ± 54). The CMR studies were diagnostic and answered the clinical questions in all patients. All infants tolerated the procedure well, and no complications were noted in any of the patients. The CMR duration ranged between 4-132 minutes (45 ± 21). The feed-and-sleep approach in selected patients obviates the need of sedation or GA for CMR in infants younger than 6 months old. Therefore, CMR can be utilized whenever echocardiography fails to provide the complete information required for the patients' management.

Abstract 17784: The Genesips Project: an NHLBI-Sponsored induced Pluripotent Stem Cell (iPSC) Resource for the Study of Cardiovascular Diseases

The study of complex cardiovascular disease (CVD) has been hampered by the lack of appropriate human cellular model systems. In response, the NHBLI sponsored the NextGen Consortium, which encompasses 9 independent efforts spanning the portfolio of NHLBI related phenotypes. The goals of the consortium include: 1. To develop and improve methods for large-scale production and characterization of induced pluripotent stem cell (iPSC) models for CVD; 2. To create a resource of iPSC lines from a large number of phenotypically and genotypically characterized individuals. Our GENESiPS project is focused on insulin resistance (IR), a condition that affects 25-33% of the US population with serious health consequences including risk of type II diabetes and CVD. Although much is known about the physiological changes occurring during IR, little is known about the molecular pathways that drive the appearance of IR. Certain mature cell types as adipocytes, endothelial cells and skeletal muscle cells have been associated with the origin, maintenance and progression of IR. IPSCs offer an unprecedented opportunity of modeling human disease in vitro. We have created iPSC lines on insulin resistant and insulin sensitive patient groups with prior GWAS genotyping. Differentiation of these iPSCs to relevant cell types is providing the opportunity to correlate insulin sensitivity and high-density genetic variation data with specific cell-based profiling. We will validate our in vitro model and study the molecular pathways that define IR and its relationship to endothelial dysfunction. Relevant to the larger scientific community the establishment of iPSC lines on over 150 individuals (3 to 6 clones per patient) that reflect the range of insulin resistance in the general population. The iPSC lines were created from erythroblasts using the non-integrative Sendai virus system, passaged to allow clearance of Sendai virus and growth in feeder free conditions. The lines have been extensively characterized for markers of pluripotency (Tra1-60), sample identity and genomic integrity. Through the NextGen consortium, these lines, as well as phenotypic and genome-wide genotyping data will be available to qualified investigators.

Use of the Hybrid Operating Room in Cardiovascular Medicine

Hybrid cardiovascular interventions, which integrate techniques of interventional cardiology with those of cardiac/vascular surgery, aim to maximize procedural benefits while minimizing invasiveness. Such hybrid procedures include transcatheter aortic valve replacement (TAVR), endovascular thoracic (TEVAR) or abdominal (EVAR) aortic repair, and combined percutaneous coronary intervention (PCI) with structural heart intervention. Some, such as TAVR, TEVAR, and EVAR, have now become the standard of care for selected patient populations. With documented improvements in outcomes, the indications for such hybrid procedures are expanding. Though some of these novel procedures can be done in either a traditional operating suite or interventional suite, neither location is ideally suited to perform many of these hybrid procedures. Proper application of hybrid techniques requires either an operating room (OR) with a high-resolution angiographic capability or an interventional suite with appropriate operating room features—the “hybrid OR.” We aim to review the concept of an integrated heart team as well as the design and implementation of the hybrid OR. Until recently, patients have been managed with a “silo” approach, with each specialty separately evaluating and treating the underlying condition. This has led in some cases to inefficient competing treatment algorithms. The growth of hybrid procedures that cross traditional specialty lines has in turn spawned the development of interdisciplinary teams. Most frequently this has manifested as a heart team to manage complex valvular heart disease as it pertains to TAVR, but the concept has also been applied to other cardiovascular conditions such as acute aortic syndromes or arrhythmias. Although an integrated team approach has long been used in oncology or transplant patients, it is now integral to the care of patients with complex cardiovascular disease. We raise the concept of the team before reviewing the hybrid OR itself because we feel the team approach is more critical to programmatic success. The …

CLINICAL AND BIOCHEMICAL PREDICTORS OF DIABETES MELLITUS MANIFESTATION AFTER MYOCARDIAL INFARCTION

Aim. To identify the most informative parameters of carbohydrate and lipid metabolism which predict the manifestation of type 2 diabetes mellitus (DM-2) within one year after myocardial infarction (MI). Material and methods. The study included 200 MI patients who underwent the assessment of glucose and insulin levels, insulin resistance (IR) index, and lipid profile at Days 1 and 12. The incidence of new DM-2 cases which manifested within a year after MI was assessed. Results. After one year after MI, incident DM-2 was diagnosed in 14,5% of the patients. It was associated with concomitant cardiovascular risk factors, adverse clinical course of acute and longer-term MI periods, and lipid metabolism disturbances. A higher risk of incident DM-2 after MI was linked to IR and an elevation in free fatty acid (FFA) levels (9,5 times or higher) during the acute MI phase. Research Institute for Complex Cardiovascular Disease Issues, Siberian Branch, Russian Academy of Medical Sciences, Kemerovo; 2 Kemerovo State Medical Academy, Kemerovo; 3Siberian State Medical University, Tomsk, Russia.

GW24-e2350 A novel mitochondrial DNA mutation associated with hypertension in 4329C>G mutation between tRNAIle and tRNAGln

ObjectivesMitochondrial DNA mutations have been reported to be involved in pathogenesis of hypertension. To investigate the relationship of mitochondrial DNA and hypertension, we did sequence analysis of patients with hypertension.MethodsIn...

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Benefit of SERCA2a Gene Transfer to Vascular Endothelial and Smooth Muscle Cells: A New Aspect in Therapy of Cardiovascular Diseases

Despite the great progress in cardiovascular health and clinical care along with marked decline in morbidity and mortality, cardiovascular diseases remain the leading causes of death and disability in the developed world. New therapeutic approaches, targeting not only systematic but also causal dysfunction, are ultimately needed to provide a valuable alternative for treatment of complex cardiovascular diseases. In heart failure, there are currently a number of trials that have been either completed or are ongoing targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) gene transfer in the context of heart failure. Recently, a phase 2 trial was completed, demonstrating safety and suggested benefit of adeno-associated virus type 1/SERCA2a gene transfer in advanced heart failure, supporting larger confirmatory trials. The experimental and clinical data suggest that, when administrated through perfusion, virus vector carrying SERCA2a can also transduce vascular endothelial and smooth muscle cells (EC and SMC) thereby improving the clinical benefit of gene therapy. Indeed, recent advances in understanding the molecular basis of vascular dysfunction point towards a reduction of sarcoplasmic reticulum Ca2+ uptake and an impairment of Ca2+ cycling in vascular EC and SMC from patients and preclinical models with cardiac diseases or with cardiovascular risk factors such as diabetes, hypercholesterolemia, coronary artery diseases, as well as other conditions such as pulmonary hypertension. In recent years, several studies have established that SERCA2a gene-based therapy could be an efficient option to treat vascular dysfunction. This review focuses on the recent finding showing the beneficial effects of SERCA2a gene transfer in vascular EC and SMC.

The Heart Team of Cardiovascular Care

The management of complex cardiovascular disease has changed markedly with the development of new strategies of care, an increasing amount of scientific evidence-based data and appropriate use criteria. Applying this plethora of information and synthesizing it for presentation and recommendations to the patient and family have assumed central importance. To facilitate this process of patient centric evidence-based care multidisciplinary Heart Teams have become identified as cornerstones. While specific strategies for implementation of these teams will vary, this broad approach will become the standard of cardiovascular care.

Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome

Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists between the fraction of population trait variance explained by such associations and total disease heritability. We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We first undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3, SRY, and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.

Committee Opinion No. 527

Advances in genetic technologies have led to the identification of hundreds of single that are associated with a variety of complex diseases, including cancer, diabetes, cardiovascular disease, and Alzheimer disease. Although personalized genomic tests that provide information regarding the risk of development of multiple diseases may be important tools in the near future, their use is not recommended outside of a clinical trial until these tests are validated as clinically useful in appropriately designed prospective studies.Testing for single-gene disorders should be approached in accordance with accepted guidelines that address the evaluation and management of these specific diseases.

Next generation sequencing in cardiovascular diseases

In the last few years, the advent of next generation sequencing (NGS) has revolutionized the approach to genetic studies, making whole-genome sequencing a possible way of obtaining global genomic information. NGS has very recently been shown to be successful in identifying novel causative mutations of rare or common Mendelian disorders. At the present time, it is expected that NGS will be increasingly important in the study of inherited and complex cardiovascular diseases (CVDs). However, the NGS approach to the genetics of CVDs represents a territory which has not been widely investigated. The identification of rare and frequent genetic variants can be very important in clinical practice to detect pathogenic mutations or to establish a profile of risk for the development of pathology. The purpose of this paper is to discuss the recent application of NGS in the study of several CVDs such as inherited cardiomyopathies, channelopathies, coronary artery disease and aortic aneurysm. We also discuss the future utility and challenges related to NGS in studying the genetic basis of CVDs in order to improve diagnosis, prevention, and treatment.

Role of Echocardiography in Sinus Venosus Atrial Septal Defect Combined with Systemic and Pulmonary Vascular Disease

We present a case of persistent left superior vena cava, anomalous right pulmonary venous connection to the right-sided superior vena cava and sinus venosus atrial septal defect detected by computed tomography (CT) pulmonary angiography and echocardiography. These defects were surgically corrected using a double-patch technique. In fact, CT can provide anatomical information about a complex anomaly in the systemic and pulmonary vasculatures. Though modern imaging techniques are useful for detecting complex cardiovascular disease, careful echocardiographic examination should be performed to diagnose complex cardiac anomalies.

From Treating Complex Coronary Artery Disease to Promoting Cardiovascular Health: Therapeutic Transitions and Challenges, 2010–2020

Cardiovascular disease (CVD) has become the most common cause of mortality worldwide. Obesity, insufficient physical exercise, diabetes, and advancing age are major risk factors for developing cardiovascular disease that are currently increasing in prevalence. Nevertheless, significant progress has recently been made in the treatment of complex cardiovascular and coronary artery disease (CAD), with pharmacological management set to assume an increasingly important role. Other timely factors, such as the development of the polypill and high-level medical and political interest in advancing cardiovascular health, are driving forces that may help to make inroads into the global cardiovascular disease burden. In this article, we critically review the key challenges that we face in the coming decade as we strive to transition and apply our growing knowledge of complex CAD to promoting global cardiovascular health.

Examining the myth of the “July Phenomenon” in surgical patients

The objective of this study is to evaluate morbidity and mortality rates in surgical patients at the beginning of the academic year. The National Surgical Quality Improvement Program database was utilized to gather data on the 10 most common inpatient operative procedures from 2005-2007. Study end points included mortality, serious adverse events (SAE), and all morbidities. Statistical analysis of outcomes was conducted examining the total population, and then stratified by operation to assess for significant differences in end points (P < .05). A total of 89,473 patients were identified. During the first academic quarter, the mortality rate was no different in the study group than the control group (2.0% vs 2.2%, P = .793). Overall SAE and morbidity rates were similar between populations (11.5% vs 11.4%, P = .697 and 18.3% vs 17.8%, P = .076, respectively). When stratified by operation, "artery bypass graft" (3.7% vs 2.9%, P = .039) and "repair bowel opening" (1.1% vs 0.6%, P = .033) subsets had increases in mortality rate. Multivariate analysis confirmed the deleterious effect of first quarter admission in only the "artery bypass graft" subset (OR = 1.35, CI 1 = .023-1.774). By in large, these data refute the "July Phenomenon." Multivariate analysis revealed patient disease to have a greater impact than timing of operation in the "repair bowel opening" subset. The "artery bypass graft" population was affected by timing of operation and the very small effect on mortality (<1%) may reflect new surgery residents being unfamiliar with the management of complex cardiovascular disease.

Epigenetic modifications: basic mechanisms and role in cardiovascular disease.

The term epigenetics was first used to refer to the complex interactions between the genome and the environment that are involved in development and differentiation in higher organisms. Today, this term is used to refer to heritable alterations that are not due to changes in DNA sequence. Rather, epigenetic modifications, or tags, such as DNA methylation and histone modification, alter DNA accessibility and chromatin structure, thereby regulating patterns of gene expression. These processes are crucial to normal development and differentiation of distinct cell lineages in the adult organism. They can be modified by exogenous influences, and as such, they can contribute to or be the result of environmental alterations of phenotype or pathophenotype. Importantly, epigenetic programming has a crucial role in the regulation of pluripotency genes, which become inactivated during differentiation. Here, we review the major mechanisms in epigenetic regulation; highlight the role of stable, long-term epigenetic modifications that involve DNA methylation; and discuss those modifications that are more flexible (short-term) and involve histone modifications, such as methylation and acetylation. We will also discuss the role of nutritional and environmental challenges in generational inheritance and epigenetic modifications, concentrating on examples that relate to complex cardiovascular diseases, and specifically dissect the mechanisms by which homocysteine modifies epigenetic tags. Lastly, we will discuss the possibilities of modifying therapeutically acquired epigenetic tags, summarizing currently available agents and speculating on future directions. Chromatin is the complex of chromosomal DNA associated with proteins in the nucleus (for review, see Campos and Reinberg1). DNA in chromatin is packaged around histone proteins, in units referred to as nucleosomes. A nucleosome has 147 base pairs of DNA associated with an octomeric core of histone proteins, which consists of 2 H3-H4 histone dimers surrounded by 2 H2A-H2B dimers. N-terminal histone tails protrude from nucleosomes into the nuclear lumen. …

1000 GENOMES: A World of Variation

Capturing roughly 95% of the common genetic variations that can be detected among the Earth's 6.9 billion individuals1 is no small task. But in the report2 published last fall of pilot data from the 1000 Genomes Project, researchers attempted to do just that and generated the most comprehensive map ever compiled of human genetic variation. Launched in 2008, the 1000 Genomes Project has set its sights on describing more than 95% of variants that occur in as few as 1%, or even fewer, of the world's people. Five major population groups are targeted—West African, European, American, and East and South Asian. “To understand a disease fully, we need to do much more extensive studies than any one such analysis should do,” says Aravinda Chakravarti, PhD, director of the Center for Complex Disease Genomics at Johns Hopkins' McKusick-Nathans Institute of Genetic Medicine. With this detailed baseline of genetic differences among living adults in hand, “it will be up to other scientists to use this … for any of the kinds of research they would want to do.” The clinical impact stemming from a deeper understanding of gene dysregulation in human disease will unfold gradually, Chakravarti adds. “But when it comes, it will be with a deep and … pervasive benefit in treatment.” Since the first draft of the human genome sequence was published a decade ago, sequencing technology and related tools have rocketed forward, making it feasible to systematically capture the genomes of many individuals and build a comprehensive catalog. In its Oct 28, 2010 issue—the same in which the 1000 Genomes pilot data was published— Nature estimated that by the end of 2011, North American laboratories alone will have sequenced approximately 9000 genomes.3 Scarcity of high-throughput sequencing equipment in most other parts of the world has led …

Using Heart Failure with Preserved Ejection Fraction to Understand an ‘Omics Approach to Evaluating Vascular Dysfunction and Cardiovascular Disease

Regulation of vascular tone is complex due to the presence of redundant mechanisms operating over multiple spatial domains (cell, tissue and organ) and influenced by various confounding factors, such as sex, age and time. As a result, the task of identifying the underlying mechanisms of vascular dysfunction associated with complex cardiovascular diseases, like heart failure with preserved ejection fraction (HFpEF), remains under explored. ‘Omics research strategies are proposed to be an effective way to navigate complicated physiology. In this review an ‘omics approach is applied to the spatial domains of HFpEF using a mechanistic “physiological map” of factors known to be associated with vascular (dys) function. The result is intended to generate hypotheses, foster robust study design, and highlight the necessity for collaborative, interdisciplinary approaches to conduct ‘omics research, which in turn is expected to facilitate the development of efficacious therapies for cardiovascular diseases such as HFpEF, where etiologies are unclear and evidence-based therapeutic strategies lacking.

Physiological homology betweenDrosophila melanogasterand vertebrate cardiovascular systems

SUMMARYThe physiology of the Drosophila melanogaster cardiovascular system remains poorly characterized compared with its vertebrate counterparts. Basic measures of physiological performance remain unknown. It also is unclear whether subtle physiological defects observed in the human cardiovascular system can be reproduced in D. melanogaster. Here we characterize the cardiovascular physiology of D. melanogaster in its pre-pupal stage by using high-speed dye angiography and optical coherence tomography. The heart has vigorous pulsatile contractions that drive intracardiac, aortic and extracellular-extravascular hemolymph flow. Several physiological measures, including weight-adjusted cardiac output, body-length-adjusted aortic velocities and intracardiac shear forces, are similar to those in the closed vertebrate cardiovascular systems, including that of humans. Extracellular-extravascular flow in the pre-pupal D. melanogaster circulation drives convection-limited fluid transport. To demonstrate homology in heart dysfunction, we showed that, at the pre-pupal stage, a troponin I mutant, held-up2 (hdp2), has impaired systolic and diastolic heart wall velocities. Impaired heart wall velocities occur in the context of a non-dilated phenotype with a mildly depressed fractional shortening. We additionally derive receiver operating characteristic curves showing that heart wall velocity is a potentially powerful discriminator of systolic heart dysfunction. Our results demonstrate physiological homology and support the use of D. melanogaster as an animal model of complex cardiovascular disease.

Multivessel peripheral revascularization for acute stroke intervention: Successful M2 bifurcation stenting and the growing case for comprehensive endovascular interventional training

A comprehensive endovascular skill set is desirable and key to successful intervention in the patient with complex cardiovascular disease. Acute stroke intervention is the next frontier for the endovascular specialist. We report a case of acute stroke intervention in a patient with severe peripheral vascular disease performed by interventional cardiologists with peripheral endovascular skills that clearly demonstrates the new paradigm of global revascularization.