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1.  Another View of Personalized Medicine: Optimizing Stent Selection on the Basis of Predicted Benefit in Percutaneous Coronary Intervention 
Drug-eluting stents (DES) decrease the risk of restenosis compared to bare metal stents (BMS) for percutaneous coronary intervention (PCI). However, their use requires patients to take prolonged dual antiplatelet therapy which increases bleeding risk, and without which, patients have an increased risk of developing stent thrombosis. In light of these competing risks, understanding which patients derive the greatest benefit of DES compared to BMS is essential for guiding therapy. We review recent efforts to predict the magnitude of the restenosis benefit of DES compared to BMS for individual patients. Understanding and predicting the likelihood of benefit for individual patients is essential to rational decision-making with regard to the type of stent to use during PCI and will serve to increase the value of the healthcare clinicians deliver.
PMCID: PMC4334450  PMID: 22841840
2.  [No title available] 
PMCID: PMC3870036  PMID: 23891554
3.  [No title available] 
PMCID: PMC3917689  PMID: 23953976
4.  [No title available] 
PMCID: PMC3948174  PMID: 23962825
5.  Atherosclerosis and interferon-γ: New insights and therapeutic targets 
Trends in cardiovascular medicine  2013;24(1):10.1016/j.tcm.2013.06.003.
Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-γ derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-γ is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-γ is a key trigger for the formation and release of reactive oxygen species. IFN-γ has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-γ have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN-γ or its receptor reduces lesion size. IFN-γ signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN-γ effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-γ and its complex effects on cells involved in atherosclerosis.
PMCID: PMC3844070  PMID: 23916809
6.  MicroRNA-29b regulation of abdominal aortic aneurysm development 
Trends in cardiovascular medicine  2013;24(1):10.1016/j.tcm.2013.05.002.
Tremendous efforts have been initiated to elucidate the molecular and pathophysiological characteristics of abdominal aortic aneurysm (AAA) disease, which is a significant contributor to morbidity and mortality in the Western world. Recently, a novel class of small non coding RNAs, called microRNAs, was identified as important transcriptional and posttranscriptional inhibitors of gene expression thought to simultaneously “fine tune” the translational output of multiple target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. Several research groups were able to identify the miR-29 family, and miR-29b in particular, as crucial regulators of –not only vascular fibrosis- but also cardiac-, kidney-, liver-, and skin-fibrosis. The current review briefly points out data indicating a causal role for miR-29 in various diseases, while focusing on its potential benefit during AAA initiation and propagation.
PMCID: PMC3815986  PMID: 23871588
7.  Calcineurin-dependent ion channel regulation in heart 
Trends in cardiovascular medicine  2013;24(1):10.1016/j.tcm.2013.05.004.
Calcineurin, a serine-threonine-specific, Ca2+-calmodulin-activated protein phosphatase, conserved from yeast to humans, plays a key role in regulating cardiac development, hypertrophy and pathological remodeling. Recent studies demonstrate that calcineurin regulates cardiomyocyte ion channels and receptors in a manner which often entails direct interaction with these target proteins. Here, we review the current state of knowledge of calcineurin-mediated regulation of ion channels in the myocardium with emphasis on the transient-outward potassium current (Ito) and L-type calcium current (ICa,L). We go on to discuss unanswered questions that surround these observations and provide perspective on future directions in this exciting field.
PMCID: PMC3830706  PMID: 23809405
8.  Compartmentalization of β-Adrenergic Signals in Cardiomyocytes 
Trends in cardiovascular medicine  2013;23(7):250-256.
Under β-adrenergic stimulation, the distribution of cAMP is highly restricted at distinct intracellular domains for compartmentalized activation of protein kinase A, which promotes selective phosphorylation of proteins for contractile responses in cardiomyocytes. This is primarily due to a concert effort between restrictions of cAMP distribution by a family of phosphodiesterases and locally anchored protein kinase A by a family of scaffold A kinase-anchoring proteins. Moreover, these regulatory mechanisms underlie cross talk between β̃ adrenergic signals and other receptor stimulated signaling cascades, which alters the compartmentalized β̃ adrenergic signals for proper contractility in myocardium. Maintaining integrity of compartmentalized β-adrenergic signals is critical for physiological cardiac function and for preventing development of cardiac diseases.
PMCID: PMC4264830  PMID: 23528751
9.  Congenital Long-QT Syndromes: A Clinical and Genetic Update From Infancy Through Adulthood 
Trends in cardiovascular medicine  2008;18(6):216-224.
Long-QT syndromes (LQTSs) have been described in all ages and are a significant cause of cardiovascular mortality, especially in structurally normal hearts. Abnormalities in transmembrane ion conduction channels and structural proteins produce these clinical syndromes, labeled LQT1-LQT12; however, genotype-positive patients still represent only about 70% of LQTSs. Future research will determine the etiology of the remaining cases, further risk-stratify the known genetic defects, improve current treatment options for these syndromes, and uncover novel therapies.
PMCID: PMC4260467  PMID: 19185812
10.  Renal denervation for refractory ventricular arrhythmias 
Trends in cardiovascular medicine  2014;24(5):206-213.
The autonomic nervous system is known to play a significant role in the genesis and persistence of arrhythmias. Neuromodulation has become a new therapeutic strategy for the treatment of ventricular arrhythmias. Catheter-based renal denervation (RDN) is being studied as a treatment option for drug-refractory hypertension. Ablation within the renal arteries, by altering efferent and afferent signaling, has the potential to improve blood pressure, as well as heart failure, atrial, and ventricular tachyarrhythmias. We present a brief review of the anatomic and pathophysiological rationale for RDN as an adjunctive treatment for ventricular tachyarrhythmias.
PMCID: PMC4254550  PMID: 25017919
11.  Nfatc1 Directs the Endocardial Progenitor Cells to Make Heart Valve Primordium 
Trends in cardiovascular medicine  2013;23(8):294-300.
Heart valves arise from the cardiac endocardial cushions located at the atrioventricular canal (AVC) and cardiac outflow tract (OFT) during development. A subpopulation of cushion endocardial cells undergoes endocardial to mesenchymal transformation (EMT) and generates the cushion mesenchyme, which is then remodeled into the interstitial tissue of the mature valves. The cushion endocardial cells that do not undertake EMT proliferate to elongate valve leaflets. During EMT and the post-EMT valve remodeling, endocardial cells at the cushions highly express nuclear factor in activated T-cell, cytoplasmic 1 (Nfatc1), a transcription factor required for valve formation in mice. In this review, we present the current knowledge of Nfatc1 roles in the ontogeny of heart valves with a focus on the fate decision of the endocardial cells in the processes of EMT and valve remodeling.
PMCID: PMC3766465  PMID: 23669445
Trends in cardiovascular medicine  2013;23(8):301-311.
Acute coronary syndromes can give rise to myocardial injury-infarction (MI), which in turn promulgates a series of cellular and extracellular events that result in left ventricular (LV) dilation and dysfunction. Localized strategies focused upon interrupting this inexorable process include delivery of bioactive molecules and stem cell derivatives. These localized treatment strategies are often delivered in a biomaterial complex in order to facilitate elution of the bioactive molecules or stem cell engraftment. However, these biomaterials can impart significant and independent effects upon the MI remodeling process. In addition, significant changes in local cell and interstitial biology within the targeted MI region can occur following injection of certain biomaterials, which may hold important considerations when using these materials as matrices for adjuvant drug/cell therapies.
PMCID: PMC3773006  PMID: 23746937
13.  Trends in Cardiovascular Engineering: Organizing the Human Heart 
Trends in cardiovascular medicine  2013;23(8):282-286.
The regulation of heart growth through the interaction of cell types, matrix molecules, and mechanical cues is poorly understood, yet is necessary for the heart to reach its proper size and function. Using mechanical load and vascular cell co-culture in combination with a tissue engineering approach, we have recently been able to generate organized human myocardium in vitro and to modulate cardiomyocyte alignment, proliferation, and hypertrophy within the engineered tissue construct; further, we measured contractile function and the force-length dependence of the engineered tissue as a whole. The goal of these studies has been to characterize in vitro models of human cardiac development and to work towards human therapeutics using organized, vascularized, contractile human cardiac tissue. This review will touch on the current state of knowledge in this field, give an overview of the results of our own recent findings, and present areas of active investigation and new directions for future research.
PMCID: PMC3791174  PMID: 23722092
14.  Fragile hearts: New insights into translational control in cardiac muscle 
Trends in cardiovascular medicine  2013;23(8):275-281.
Current investigations focused on RNA-binding proteins in striated muscle, which provide a scenario whereby muscle function and development are governed by the interplay of post-transcriptional RNA regulation, including transcript localization, splicing, stability, and translational control. New data have recently emerged, linking the RNA-binding protein FXR1 to the translation of key cytoskeletal components such as talin and desmoplakin in heart muscle. These findings, together with a plethora of recent reports implicating RNA-binding proteins and their RNA targets in both basic aspects of muscle development and differentiation as well as heart disease and muscular dystrophies, point to a critical role of RNA-based regulatory mechanisms in muscle biology. Here we focus on FXR1, the striated muscle-specific member of the Fragile X family of RNA-binding proteins and discuss its newly reported cytoskeletal targets as well as potential implications for heart disease.
PMCID: PMC4142197  PMID: 23582851
15.  Protein disulfide isomerase as an antithrombotic target 
Trends in cardiovascular medicine  2013;23(7):264-268.
Protein disulfide isomerase (PDI) is a ubiquitously expressed oxidoreductase required for proper protein folding. It is highly concentrated in the endoplasmic reticulum, but can also be released into the extracellular environment. Several in vivo thrombosis models have demonstrated that vascular PDI secreted by platelets and endothelial cells is essential for normal thrombus formation. Inhibition of extracellular PDI thus represents a potential strategy for antithrombotic therapy. Yet this approach requires the discovery of well-tolerated PDI inhibitors. A recent high throughput screen identified the commonly ingested flavonoid, quercetin-3-rutinoside, as an inhibitor of PDI. Quercetin-3-rutinoside blocked thrombus formation at concentrations that are commonly ingested as nutritional supplements. The observation that a compound with Generally Recognized As Safe status inhibits PDI and blocks thrombosis in animal models forms a rationale for clinical trials evaluating PDI inhibitors as a new class of antithrombotics.
PMCID: PMC3701031  PMID: 23541171
16.  Mediating Lipid Biosynthesis: Implications for Cardiovascular Disease 
Trends in cardiovascular medicine  2013;23(7):269-273.
Dysregulation of lipid homeostasis is a risk factor for cardiovascular disease (CVD). Thus, understanding the molecular mechanisms of maintaining lipid homeostasis may aid the discovery of novel targets for treating CVD. MED15 and Cyclin-dependent kinase-8 (CDK8) are subunits of the Mediator complex, which contains multiple proteins and functions as a transcriptional cofactor. Mediator can positively or negatively regulate gene expression, depending on the contexts and its associated transcription factors. Recent studies revealed a critical role of MED15 and CDK8 in regulating sterol regulatory element-binding protein (SREBP) transcription factors, which are master activators for genes that are responsible for lipid biosynthesis. Here, we review the function of MED15 and CDK8 in regulating lipid homeostasis and discuss the implications for CVD.
PMCID: PMC3744615  PMID: 23562092
MED15; CDK8; SREBP; Transcription; Lipid; Phosphorylation; CVD; Atherosclerosis
17.  Re-Engineered Stromal Cell-Derived Factor-1α (SDF) and the Future of Translatable Angiogenic Polypeptide Design 
Trends in cardiovascular medicine  2012;22(6):139-144.
Smaller engineered analogs of angiogenic cytokines may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and most importantly the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the SDF molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low molecular weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than recombinant human SDF both in vitro and in a murine model of ischemic heart failure.
PMCID: PMC4155938  PMID: 22902182
18.  Molecular imaging: The key to advancing cardiac stem cell therapy 
Trends in cardiovascular medicine  2013;23(6):201-210.
Cardiac stem cell therapy continues to hold promise for the treatment of ischemic heart disease despite the fact that early promising pre-clinical findings have yet to be translated into consistent clinical success. The latest human studies have collectively identified a pressing need to better understand stem cell behavior in humans and called for more incorporation of noninvasive imaging techniques into the design and evaluation of human stem cell therapy trials. This review discusses the various molecular imaging techniques validated to date for studying stem cells in living subjects, with a particular emphasis on their utilities in assessing the acute retention and the long-term survival of transplanted stem cells. These imaging techniques will be essential for advancing cardiac stem cell therapy by providing the means to both guide ongoing optimization and predict treatment response in humans.
PMCID: PMC3799844  PMID: 23561794
19.  HDAC-dependent Ventricular Remodeling 
Trends in cardiovascular medicine  2013;23(6):229-235.
Heart failure, a syndrome culminating the pathogenesis of many forms of heart disease, is highly prevalent and projected to be increasingly so for years to come. Major efforts are directed at identifying means of preventing, slowing, or possibly reversing the unremitting progression of pathological stress leading to myocardial injury and ultimately heart failure. Indeed, despite widespread use of evidence-based therapies, heart failure morbidity and mortality remain high. Recent work has uncovered a fundamental role of reversible protein acetylation in the regulation of many biological processes, including pathological remodeling of the heart. This reversible acetylation is governed by enzymes that attach (histone acetyltransferases, HAT) or remove (histone deacetylases, HDACs) acetyl groups. In the case of the latter, small molecule inhibitors of HDACs are currently being tested for a variety of oncological indications. Now, evidence has revealed that HDAC inhibitors blunt pathological cardiac remodeling in the settings of pressure overload and ischemia/reperfusion, diminishing the emergence of heart failure. Mechanistically, HDAC inhibitors reduce stress-induced cardiomyocyte death, hypertrophy, and ventricular fibrosis. Looking to the future, HDAC inhibitor therapy may emerge as a novel means of arresting the untoward consequences of pathological cardiac stress, conferring clinical benefit to the millions of patients with heart failure.
PMCID: PMC3688696  PMID: 23499301
heart failure; hypertrophy; remodeling; histone deacetylases
20.  The Perinexus: Sign-Post on the Path to a New Model of Cardiac Conduction? 
Trends in cardiovascular medicine  2013;23(6):222-228.
The perinexus is a recently identified microdomain surrounding cardiac gap junctions that contains elevated levels of connexin43 and the sodium channel protein Nav1.5. Ongoing work has established a role for the perinexus in regulating gap junction aggregation. However, recent studies have raised the possibility of a perinexal contribution at the gap junction cleft to intercellular propagation of action potential via non-electrotonic mechanisms. The latter possibility could modify current theoretical understanding of cardiac conduction, help explain paradoxical experimental findings, and open up entirely new avenues for antiarrhythmic therapy. We review recent structural insights into the perinexus and its potential novel functional role in cardiac excitation spread, highlighting presently unanswered questions, the evidence for ephaptic conduction in the heart and how structural insights may help complete this picture.
PMCID: PMC3686992  PMID: 23490883
Perinexus; Gap Junction; Connexin; Sodium Channel; Nav1.5; Ephaptic; Intercalated Disk; Conduction
21.  Tuning the molecular giant titin through phosphorylation-role in health and disease 
Trends in cardiovascular medicine  2013;23(5):165-171.
Titin is a giant multi-functional filament that spans the half sarcomere. Titin’s extensible I-band region functions as a molecular spring that provides passive stiffness to cardiac myocytes. Elevated diastolic stiffness is found in a large fraction of heart failure patients and thus understanding the normal mechanisms and pathophysiology of passive stiffness modulation is clinically important. Here we provide first a brief general background on titin including what is known about titin isoforms and then focus on recently discovered post-translational modifications of titin that alter passive stiffness. We discuss the various kinases that have been shown to phosphorylate titin and address the possible roles of titin phosphorylation in cardiac disease, including heart failure with preserved ejection fraction (HFpEF).
PMCID: PMC3622841  PMID: 23295080
22.  3D engineered cardiac tissue models of human heart disease: Learning more from our mice☆ 
Mouse engineered cardiac tissue constructs (mECTs) are a new tool available to study human forms of genetic heart disease within the laboratory. The cultured strips of cardiac cells generate physiologic calcium transients and twitch force, and respond to electrical pacing and adrenergic stimulation. The mECT can be made using cells from existing mouse models of cardiac disease, providing a robust readout of contractile performance and allowing a rapid assessment of genotype–phenotype correlations and responses to therapies. mECT represents an efficient and economical extension to the existing tools for studying cardiac physiology. Human ECTs generated from iPSCMs represent the next logical step for this technology and offer significant promise of an integrated, fully human, cardiac tissue model.
PMCID: PMC4066654  PMID: 23295081
23.  Cardioprotective Signaling by Endothelin 
Trends in cardiovascular medicine  2008;18(7):233-239.
The endothelin axis promotes survival signaling pathways in the heart, inviting the idea to use antagonists of endothelin signaling for the treatment of heart failure. Promising results from animal trials, however, failed to show beneficial effects in heart failure patients. Here we review the role of major signaling pathways in the heart that are involved in cell survival initiated by ET-1. These pathways include MAPK, PI3K/AKT,NF κB and calcineurin signaling. A better understanding of endothelin mediated signaling in cardiac cell survival may allow a re-evaluation of endothelin receptor antagonists in the treatment of heart failure.
PMCID: PMC4048746  PMID: 19232951
24.  Anti-angiogenic Activity of rPAI-123 and Vasa Vasorum Regression 
Trends in cardiovascular medicine  2013;23(4):114-120.
The vasa vasorum are a unique network of vessels that become angiogenic in response to changes in the vessel wall. Structural studies, using various imaging modalities, show that the vasa vasorum form a plexus of microvessels during the atherosclerotic disease process. The events that stimulate vasa vasorum neovascularization remain unclear. Anti-angiogenic molecules have been shown to inhibit/regress the neovascularization; they provide significant insight into vasa vasorum function, structure and specific requirements for growth and stability. This review discusses evidence for and against potential stimulators of vasa vasorum neovascularization. Anti-angiogenic rPAI-123, a truncated isoform of plasminogen activator inhibitor-1 (PAI-1) stimulates a novel pathway for regulating plasmin activity. This mechanism contributes significantly to vasa vasorum regression/collapse and will be discussed as a model of regression.
PMCID: PMC3624061  PMID: 23313168
25.  Cardiovascular Complications Associated with Novel Angiogenesis Inhibitors: Emerging Evidence and Evolving Perspectives 
Trends in cardiovascular medicine  2013;23(4):104-113.
Novel cancer therapies targeting tumor angiogenesis have revolutionized treatment options in a variety of tumors. Specifically, VEGF signaling pathway (VSP) inhibitors have been introduced into clinical practice at a rapid pace over the last decade. It is becoming increasingly clear that VSP inhibitors can cause cardiovascular toxicities including hypertension, thrombosis, and heart failure. This review highlights these toxicities and proposes several strategies in their prevention and treatment. However, we recognize the dearth of data in this area and advocate a multi-disciplinary approach involving cardiologists and oncologists, as well as clinical and translational studies, in understanding and treating VSP-inhibitor associated toxicities.
PMCID: PMC3621011  PMID: 23290365

Results 1-25 (133)