Posts Tagged ‘Columbia University Medical Center’

Systems Biology Analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

Posted in Artificial Intelligence in CANCER, Artificial Intelligence in Health Care - Tools & Innovations, Artificial Intelligence in Medicine - Applications in Therapeutics, Big Data, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cell Biology, Cell Biology, Signaling & Cell Circuits, Clinical & Translational, Clinical Genomics, Genomic Expression, Intelligent Information Systems, tagged activation of transcription factors, Artificial intelligence, Artificial Intelligence & Clinical Trials, Biological Networks, Columbia University Medical Center, DarwinHealth, mutational analysis, RNA-Seq, transcription control on July 14, 2020| Leave a Comment »

Systems Biology analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

Curator: Stephen J. Williams, Ph.D.

In the June 2020 issue of the journal Science, writer Roxanne Khamsi has an interesting article “Computing Cancer’s Weak Spots; An algorithm to unmask tumors’ molecular linchpins is tested in patients”[1], describing some early successes in the incorporation of cancer genome sequencing in conjunction with artificial intelligence algorithms toward a personalized clinical treatment decision for various tumor types. In 2016, oncologists Amy Tiersten collaborated with systems biologist Andrea Califano and cell biologist Jose Silva at Mount Sinai Hospital to develop a systems biology approach to determine that the drug ruxolitinib, a STAT3 inhibitor, would be effective for one of her patient’s aggressively recurring, Herceptin-resistant breast tumor. Dr. Califano, instead of defining networks of driver mutations, focused on identifying a few transcription factors that act as ‘linchpins’ or master controllers of transcriptional networks withing tumor cells, and in doing so hoping to, in essence, ‘bottleneck’ the transcriptional machinery of potential oncogenic products. As Dr. Castilano states

“targeting those master regulators and you will stop cancer in its tracks, no matter what mutation initially caused it.”

It is important to note that this approach also relies on the ability to sequence tumors by RNA-seq to determine the underlying mutations which alter which master regulators are pertinent in any one tumor. And given the wide tumor heterogeneity in tumor samples, this sequencing effort may have to involve multiple biopsies (as discussed in earlier posts on tumor heterogeneity in renal cancer).

As stated in the article, Califano co-founded a company called Darwin-Health in 2015 to guide doctors by identifying the key transcription factors in a patient’s tumor and suggesting personalized therapeutics to those identified molecular targets (OncoTarget™). He had collaborated with the Jackson Laboratory and most recently Columbia University to conduct a $15 million 3000 patient clinical trial. This was a bit of a stretch from his initial training as a physicist and, in 1986, IBM hired him for some artificial intelligence projects. He then landed in 2003 at Columbia and has been working on identifying these transcriptional nodes that govern cancer survival and tumorigenicity. Dr. Califano had figured that the number of genetic mutations which potentially could be drivers were too vast:

A 2018 study which analyzed more than 9000 tumor samples reported over 1.5 million mutations[2]

and impossible to develop therapeutics against. He reasoned that you would just have to identify the common connections between these pathways or transcriptional nodes and termed them master regulators.

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Chen H, Li C, Peng X, et al. Cell. 2018;173(2):386-399.e12.

Abstract

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

A diagram of how concentrating on these transcriptional linchpins or nodes may be more therapeutically advantageous as only one pharmacologic agent is needed versus multiple agents to inhibit the various upstream pathways:

From: Khamsi R: Computing cancer’s weak spots. Science 2020, 368(6496):1174-1177.

VIPER Algorithm (Virtual Inference of Protein activity by Enriched Regulon Analysis)

The algorithm that Califano and DarwinHealth developed is a systems biology approach using a tumor’s RNASeq data to determine controlling nodes of transcription. They have recently used the VIPER algorithm to look at RNA-Seq data from more than 10,000 tumor samples from TCGA and identified 407 transcription factor genes that acted as these linchpins across all tumor types. Only 20 to 25 of them were implicated in just one tumor type so these potential nodes are common in many forms of cancer.

Other institutions like the Cold Spring Harbor Laboratories have been using VIPER in their patient tumor analysis. Linchpins for other tumor types have been found. For instance, VIPER identified transcription factors IKZF1 and IKF3 as linchpins in multiple myeloma. But currently approved therapeutics are hard to come by for targets with are transcription factors, as most pharma has concentrated on inhibiting an easier target like kinases and their associated activity. In general, developing transcription factor inhibitors in more difficult an undertaking for multiple reasons.

Network-based inference of protein activity helps functionalize the genetic landscape of cancer. Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A:. Nature genetics 2016, 48(8):838-847 [3]

Abstract

Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible. To address this problem we introduce and experimentally validate a new algorithm, VIPER (Virtual Inference of Protein-activity by Enriched Regulon analysis), for the accurate assessment of protein activity from gene expression data. We use VIPER to evaluate the functional relevance of genetic alterations in regulatory proteins across all TCGA samples. In addition to accurately inferring aberrant protein activity induced by established mutations, we also identify a significant fraction of tumors with aberrant activity of druggable oncoproteins—despite a lack of mutations, and vice-versa. In vitro assays confirmed that VIPER-inferred protein activity outperforms mutational analysis in predicting sensitivity to targeted inhibitors.

Figure 1

Schematic overview of the VIPER algorithm From: Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A: Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nature genetics 2016, 48(8):838-847.

(a) Molecular layers profiled by different technologies. Transcriptomics measures steady-state mRNA levels; Proteomics quantifies protein levels, including some defined post-translational isoforms; VIPER infers protein activity based on the protein’s regulon, reflecting the abundance of the active protein isoform, including post-translational modifications, proper subcellular localization and interaction with co-factors. (b) Representation of VIPER workflow. A regulatory model is generated from ARACNe-inferred context-specific interactome and Mode of Regulation computed from the correlation between regulator and target genes. Single-sample gene expression signatures are computed from genome-wide expression data, and transformed into regulatory protein activity profiles by the aREA algorithm. (c) Three possible scenarios for the aREA analysis, including increased, decreased or no change in protein activity. The gene expression signature and its absolute value (|GES|) are indicated by color scale bars, induced and repressed target genes according to the regulatory model are indicated by blue and red vertical lines. (d) Pleiotropy Correction is performed by evaluating whether the enrichment of a given regulon (R₄) is driven by genes co-regulated by a second regulator (R₄∩R₁). (e) Benchmark results for VIPER analysis based on multiple-samples gene expression signatures (msVIPER) and single-sample gene expression signatures (VIPER). Boxplots show the accuracy (relative rank for the silenced protein), and the specificity (fraction of proteins inferred as differentially active at p < 0.05) for the 6 benchmark experiments (see Table 2). Different colors indicate different implementations of the aREA algorithm, including 2-tail (2T) and 3-tail (3T), Interaction Confidence (IC) and Pleiotropy Correction (PC).

Real Time Coverage @BIOConvention #BIO2019: Keynote: Siddhartha Mukherjee, Oncologist and Pulitzer Author; June 4 9AM Philadelphia PA

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, interventional oncology, Interviews with Scientific Leaders, tagged #endcancer, @DrSidMukherjee, Columbia University Medical Center, Conference Coverage with Social Media, Immune-Oncology Drug Discovery, immunooncology, interviews with notable physician, interviews with notable scientist, scientific leaders on June 4, 2019| Leave a Comment »

Real Time Coverage @BIOConvention #BIO2019: Keynote: Siddhartha Mukherjee, Oncologist and Pulitzer Author; June 4 9AM Philadelphia PA

Reporter: Stephen J. Williams, PhD. @StephenJWillia2

Hematologist and oncologist Siddhartha Mukherjee was born in New Delhi, India. He holds a BS in biology from Stanford University, a DPhil in immunology from Oxford University (where he was a Rhodes Scholar), and an MD from Harvard Medical School. He completed his internal medicine residency and an oncology fellowship at Massachusetts General Hospital. Dr. Murkherjee is an assistant professor of medicine at Columbia University Medical Center. He lives in Manhattan with his wife, artist Sarah Sze, and their two daughters. His Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer, tells the story of cancer from its first description in an ancient Egyptian scroll to the gleaming laboratories of modern research institutions. A three-part documentary series based on the book, directed by Barak Goodman and executive produced by Ken Burns, debuts on PBS stations March 30 and continues on March 31 and April 1. The film interweaves a sweeping historical narrative with intimate stories about contemporary patients and an investigation into the latest scientific breakthroughs. He has also written the award winning book “The Gene: An Intimate History” and is Founder of Vor Biopharma, who had just published on their CD33 engineered hematopoetic stem cells as an immunooncology therapy VOR33.

Hon. James C. Greenwood- former Congressional representative and Founder CEO of BIO: moderator

Greenwood: Never have the threats from DC to innovation in the biotech field been so great. Focused on some great recent innovations and successes in gene therapy. Although the cost high, father of two LMR retinopathy patients said if his sons had to go through a lifetime of constant care it would cost much more than the gene therapy from Spark cost. Politicians need to realize that medicines that completely cure diseases are worth much more. They should meet in the middle with respect to developing a new payer model that will not hurt innovation.

Dr. Mukherjee: He go into oncology from a virology PhD because he liked to understand the human aspect

of disease. As an oncologist he gets to interact more closely with patients. The oncology horizon is always changing. He likened his view of oncology and cancer as a pyramid with prevention the base, then early detection then therapy at top.

We haven’t found preventable human carcinogens, none that is highly proven causal

This will be the next challenge for cancer researchers, to figure out why we can’t identify these preventable carcinogens.

Our affiliate Vor Biopharma, co-founded by @DrSidMukherjee, published the results of a preclinical study of VOR33 in @PNASNews. Read about Vor’s novel approach to treating #cancer via engineered hematopoietic stem cells: https://t.co/6zvt0lWYjO #immunotherapy

— PureTech, Developing BIG Medicines (@PureTechH) May 29, 2019

The link to the PNAS paper on VOR33 can be found here: https://www.pnas.org/content/early/2019/05/23/1819992116

Please follow on Twitter using these @ handles and # hashtags

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# Hashtags

#BIO2019 (official meeting hashtag)

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Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders at https://www.amazon.com/dp/B078313281 – electronic Table of Contents

Jennifer Doudna and NPR science correspondent Joe Palca, several interviews

Practicing Oncology: Medscape Editor-in-Chief Eric J. Topol, MD interviews Siddhartha Mukherjee, MD, PhD

Eric Topol interviews Al Gore on Genomics and Privacy

Dr. Mercola Interviews Dr. Saul About Beta-Blockers

Volume Two: Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders

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Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Coagulation Therapy and Internal Bleeding, Electrophysiology, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Technology Transfer: Biotech and Pharmaceutical, tagged Cardiogenic Shock, Cardiovascular Disorders, Columbia University Medical Center, Conditions and Diseases, Electrocardiography, Heart disease, myocardial infarction, Thoratec, United States, Ventricular assist device on June 18, 2013| 7 Comments »

Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

Writer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

A ventricular assist device (VAD) is an implantable mechanical pump that helps pump blood from the lower chambers of your heart (the ventricles) to the rest of your body. VADs are used in people who have weakened hearts or heart failure. Although VADs can be placed in the left, right or both ventricles of your heart, they are most frequently used in the left ventricle. When placed in the left ventricle they are called left ventricular assist devices (LVADs).

You may have a VAD implanted while you wait for a heart transplant or for your heart to become strong enough to effectively pump blood on its own. Your doctor may also recommend having a VAD implanted as a long-term treatment if you have heart failure and you’re not a good candidate for a heart transplant.

The procedure to implant a VAD requires open-heart surgery and has serious risks. However, a VAD can be lifesaving if you have severe heart failure.

http://www.mayoclinic.com/health/lvad/MY01077

This is an assessment of the development and progression of cardiogenic shock and review of the use of ventricular assist devices in that setting. It is another piece of the chapter on cardiothoracic surgical management at Columbia University Medical Center, New York, NY.

Heart Lung. 2012 Sep-Oct;41(5):500-4. http://dx.doi.org/10.1016/j.hrtlng.2012.03.007.___Epub 2012 May 16.

A stepwise progression in the treatment of cardiogenic shock.

Pollack A, Uriel N, George I, Kodali S, Takayama H, Naka Y, Jorde U.

Source

Department of Medicine, New York Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA.

Abstract

Cardiogenic shock remains a deadly complication of acute myocardial infarction (MI). Early revascularization, inotropic support, and intraaortic balloon counterpulsation are the mainstays of treatment, but these are not always sufficient. New mechanical approaches, both percutaneous and surgical, are available in this high-risk population. We present a case of a young woman with a massive anterior wall MI and subsequent cardiogenic shock who was treated with advanced mechanical circulatory support. This case serves as an illustration of the stepwise escalation of mechanical support that can be applied in a patient with an acute MI complicated by refractory cardiogenic shock. We also review the literature with regard to the use of percutaneous left ventricular assist devices in the setting of cardiogenic shock.

PMID: 22608034

Care of the Critically Ill: A Stepwise Progression in the Treatment of Cardiogenic Shock.

Pollack A, Uriel N, George I, Kodali S, Takayama H, Naka Y, Jorde U

J Heart & Lung 2012; 41:500-504.

http://dx.doi.org/10.1016/j.hrtlng.2012.03.007

Initial Presentation

A 21-year-old woman with a history of migraine headaches was admitted to the hospital with nonradiating substernal chest pain onset that morning. When she presented to another hospital she had a normal electrocardiogram (EKG) and was discharged. When the patient’s chest discomfort became crushing she presented again to the same hospital where her EKG revealed ST-segment elevations in an anterolateral distribution. Her peak (hs) troponin was 229 ng/mL and peak creatinine kinase was 6900 U/L. This was an elevation of CK far out of proportion to the troponin increase (suggestive of decreased peripheral circulation with massive release of CK from muscle). There was no family history of early myocardial infarction (MI), sudden cardiac death, clotting disorders, or hypercholesterolemia. She had been taking amitriptyline for migraines and oral contraceptives for 3 years. The patient developed significant hypotension, after she was given metoprolol and morphine, for which dobutamine and dopamine were administered. Medication was switched to norepinephrine because of excessive tachycardia. Cardiac catheterization was performed emergently approximately 12 hours after the onset of the patient’s chest pain.

Thrombectomy of an angiographically identified clot in the proximal portion of the left anterior descending artery was performed, followed by placement of a bare metal stent with no residual occlusion. An intraaortic balloon bump (IABP) was placed. The initial transthoracic echocardiogram revealed an ejection fraction of 25% and global hypokinesis with regional wall motion abnormalities, worst in the anterior, apical, and lateral walls. She was intubated and required significant hemodynamic support with norepinephrine. Her antiplatelet regimen consisted of oral aspirin, clopidogrel, and intravenous eptifibatide. The patient was transferred to the New York Presbyterian Hospital/Columbia University Medical Center approximately 12 hours after revascularization.

Transfer to NY Presbyteran Columbia Hospital

On arrival, the patient was intubated and sedated. Her blood pressure was 80/51mmHg, pulse rate was 140 beats/min, and oral temperature was 101F. On examination, she was tachycardic with warm extremities. The jugular veins were not distended. Her lactate was 7.0 mmol/L. (If she was so severely hypotensive with lactic acidemia, possibly from impaired liver and/or muscle circulation with aerobic glycolysis, then why was the temperature 101 deg F?) The patient was not tested for procalcitonin (Brahms, BioMerieux), but sepsis is now considered bacterial or abacterial. Whether there was release of bacterial endotoxin secondary to poor decreased circulation in the superior mesenteric artery is not known, which complicates the situation more. In a study of acute phase changes in liver proteins by Bernstein and associates [Transthyretin as a marker to predict outcome in critically ill patients. Devakonda A, George L, Raoof S, Esan A, Saleh A, Bernstein LH. Clin Biochem 2008; 41(14-15):1126-1130. ICID: 939927], and another on procalcitonin and sepsis [The role of procalcitonin in the diagnosis of sepsis and patient assignment to medical intensive care. Bernstein LH, Devakonda A, Engelman E, Pancer G, Ferrar J, Rucinski J, Raoof S, George L, Melniker L. J Clin Ligand Assay] there was a notable case of negative bacterial culture in a patient with highly elevated procalcitonin, considered a reliable early indicator of sepsis.

Procalcitonin (PCT) is a sensitive and specific inflammation marker, which can be used to detect both inflammatory infections and noninflammatory complications in postsurgical monitoring of patients after cardiac surgery using extracorporeal circulation. The optimum cut-off value for PCT levels, as a predictor of postoperative complications, appears to be 1.2 ng/mL with a sensitivity of 80% and a specificity of 90%. PCT may be used to monitor response to therapy because blood concentrations increase in an inflammatory disease relapse. Importance of procalcitonin in post-cardiosurgical patients. Topolcan O, Bartunek L, Holubec Jr L, Polivkova V, eta al. Journal of Clinical Ligand Assay 2008; 31(1-4): 57-60.]This might be expected to be associated with a CRP increase over 50-70 mg/ml. In addition, the hemogram would have been of some interest, perhaps raising the question of whether the cardiovascular impairment triggered other events [Validation and Calibration of the Relationship between Granulocyte Maturation and the Septic State. Bernstein LH and Rucinski J. Clin Chem Lab Med 2011; 49. Walter de Gruyter . http://dx.doi.org/10.1515cclm.2011.688. Converting Hematology Based Data into an Inferential Interpretation. Bernstein LH, David G, Rucinski J and Coifman RR. In Hematology – Science and Practice, 2012. Chapter 22, pp 541-552. InTech Open Access Publ. Croatia].

A chest radiograph showed pulmonary edema. Her EKG revealed sinus tachycardia at 121 beats/min with ST-segment elevation of 3 mm in leads V1 to V4 and poor R-wave progression throughout the precordial leads with pathologic Q waves in V1 to V6, I, and aVL. Eptifibatide (Integrilin, Merck & Co., Inc., Whitehouse Station, NJ) was stopped, and norepinephrine was continued at 20 mg/min. Dobutamine 2.5 mg/min and broad-spectrum antibiotics were administered. During the next 4 hours, the patient’s mean arterial pressure fluctuated between 60 and 70 mm Hg with a heart rate between 120 and 140 beats/min on 20 mg/min of norepinephrine, 2.5 mg/min of dobutamine, and the IABP. Rapid escalation of mechanical support with a left ventricular assist device (LVAD) was deemed necessary. Right-sided heart catheterization after placement of an Impella 2.5 assist device (ABIOMED, Inc.) revealed a cardiac output of 3.3 L/min and a cardiac index (CI) of 2.1 L/min/m2, despite addition of 3 ug/min and 4 U/h of vassopressin.

Day 2

On the second day after transfer she was severely hyponatremic, but her plasma sodium stabilized at 131 to 138 mmol/L after discontinuing the vasopressin. She also developed significant bleeding at the site of the Impella and hemolysis requiring several blood transfusions. Her hemoglobin on transfer was 10.4 g/dL, which trended down to 7.8 g/dL after Impella placement. The patient’s lactate dehydrogenase was 1980 U/L (probably reflecting poor liver perfusion), and total bilirubin was 2.6 mg/dL on day 2 of her hospitalization compared with 1.1 mg/dL on transfer.

Day 3

After the Impella device was removed on day 3 because of persistent bleeding, the patient’s hemoglobin, bilirubin, and platelet count stabilized, but while the patient was able to maintain end-organ perfusion initially as manifested by a normal creatinine, as the day progressed, the patient’s systemic blood pressure trended downward and urine output decreased, and she could not tolerate discontinuation of the vasoactive agents being administered. Pulmonary hypertension developed with a rate-dependent cardiac output as manifested by persistent tachycardia, and had an ejection fraction of 20% with severe hypokinesis of all segments except the basal inferior and inferolateral walls. As a consequence of the enduring cardiogenic shock and the low likelihood for recovery of left ventricular function, it was evident the patient required long-term mechanical support. A continuous flow LVAD (HeartMate II; Thoratec Corporation) was implanted as a rescue therapy, and the patient was emergently listed for transplantation.

Recovery

A comprehensive heart failure regimen was introduced, and the patient was discharged with warfarin 25 days after her transfer. A comprehensive hypercoagulability workup performed while the patient was receiving anticoagulation with negative results. Aside from oral contraceptive use, no other obvious risk factor for an acute arterial thrombosis could be identified, which is not surprising given that up to 40% of all thrombotic events occur in patients without a recognizable risk factor. Early revascularization, inotropic support, and intraaortic balloon counterpulsation are the mainstays of treatment, but these are not always sufficient. New mechanical approaches, both percutaneous and surgical, are available in this high-risk population. This case serves as an illustration of the stepwise escalation of mechanical support that can be applied in a patient with an acute MI complicated by refractory cardiogenic shock. We also review the literature with regard to the use of percutaneous left ventricular assist devices in the setting of cardiogenic shock.

Recommendation

The authors recommend the following protocol for patients with cardiogenic shock superimposed on acute MI. Treatment of cardiogenic shock. PCI, percutaneous coronary intervention; IABP, intraaortic balloon pump; VAD, ventricular assist device; VA-ECMO, venoarterial extracorporeal membrane oxygenation; OHT, orthotopic heart transplantation; pVAD, percutaneous ventricular assist device. It is important to note that it includes immediate revascularization in conjunction with IABP placement. In patients with refractory cardiogenic shock who are unable to be weaned from the IABP, mechanical circulatory support using a percutaneous or surgical device is the next essential measure to be taken. The type of mechanical support to be used depends on many factors, including the reversibility of the shock state, chances of ventricular recovery, and risk of bleeding. Mechanical circulatory support with left ventricular assists devices can improve cardiac performance and reduce myocardial ischemic injury. Principle mechanisms include unloading of the left ventricle, thereby decreasing myocardial oxygen demand and improvement of systemic hypotension, thus increasing coronary perfusion.

Although there were complications related to the use of the device, its deployment resulted in the improvement of the patient’s surgical candidacy by virtue of maintaining her end-organ function. After the removal of the Impella device, we thought the left ventricle in this patient would not recover, and for this reason, we chose a definitive surgical procedure as opposed to alternative temporary support device. Clinical studies focusing on the use of VA-ECMO in refractory cardiogenic shock after an acute MI are limited. Observational and retrospective series have thus far demonstrated a high mortality rate in these patients. However, a recent retrospective study of 33 patients who received ECMO support for advanced refractory cardiogenic shock after an acute MI demonstrated a mortality rate of 46% and 52% at 30 days and 1 year, respectively. In addition to mny complications with VA-ECMO, the procedure also can lead to increased afterload from the retrograde flow of peripheral cannulation., which may to lead to increased left ventricular pressure and wall stress, thereby compromising myocardial recovery and worsening pulmonary edema, both of which were major concerns

in this patient.

Conclusions

This case demonstrates that a sequential approach using percutaneous mechanical support as a bridge to surgical mechanical support is feasible in this high-risk population (Figure ). Advantages of percutaneous mechanical support include its rapid and straightforward placement. Disadvantages include its limited cardiac output and bleeding. Future technology should focus on a device that is capable of providing significant cardiac output and that can be easily placed, like the Impella. Such a device could alter the natural history of intractable cardiogenic shock.

University of Miami Hospital sends team to Panama to save NCIS agent’s life (miamiherald.com)
The SOAP-II trial: First-line vasopressor for shock management [Classics Series] (2minutemedicine.com)
Abiomed (ABMD) Impella Approved for Reimbursement in the Netherlands (streetinsider.com)
Thoratec Announces Presentations At Upcoming Investor Conferences (sys-con.com)
Abiomed gets reimbursement for Impella heart pump (bizjournals.com)

Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, PCI, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, Uncategorized, Valves & Tools, tagged Angina pectoris, Aortic valve, Aortic valve replacement, CABG, Cardiovascular disease, Columbia University Medical Center, Coronary artery bypass surgery, Coronary artery disease, Edwards Lifesciences Corporation, Food and Drug Administration, Percutaneous coronary intervention, surgery, TAVR on June 17, 2013| 12 Comments »

Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Writer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Significant, defined as a greater than 50 percent narrowing, left main coronary artery disease (LMCAD) is found in 4 to 6 percent of all patients who undergo coronary arteriography [1]. When present, it is associated with multivessel coronary artery disease (MVCAD) about 70 percent of the time [2,3].

Most patients are symptomatic and at high risk of cardiovascular events, since occlusion of this vessel compromises flow to at least 75 percent of the left ventricle, unless it is protected by collateral flow or a patent bypass graft to either the left anterior descending or circumflex artery. Studies performed before revascularization with coronary artery bypass graft surgery (CABG) became the standard of care revealed a poor prognosis for these patients, with three-year survival as low as 37 percent [4]. CABG, when directly compared to medical therapy, is associated with significantly better cardiovascular outcomes, including mortality [5].

Percutaneous coronary intervention (PCI) with stenting has generally been restricted to such patients considered inoperable or at high risk for CABG, or with prior CABG and at least one patent graft to the left anterior descending or circumflex artery (so-called “protected” left main disease). Graft patency is important in this setting in the event of acute or late closure after PCI. However, evidence is increasing to support the use of PCI with stenting in some cases. (See ‘PCI versus CABG’ below.)

Asymptomatic patients with left main lesions felt to not be hemodynamically significant should be managed with preventative therapies. Patients with anginal symptoms attributable to lesions elsewhere should be managed with therapies similar to those used in other patients with coronary artery disease. (See “Overview of the care of patients with stable ischemic heart disease”.)

This topic will discuss most aspects of the management of patients with LMCAD. The approach to patients with multivessel coronary artery disease without LMCAD is discussed elsewhere. (See “Bypass surgery versus percutaneous intervention in the management of stable angina pectoris: Recommendations”.)

http://www.uptodate.com/contents/management-of-left-main-coronary-artery-disease

Catheter Cardiovasc Interv. 2013 Feb 14.

http://dx.doi.org/10.1002/ccd.24865. [Epub ahead of print]

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Paradis JM, George I, Kodali S.

Source

Columbia University Medical Center, New York, New York; Cardiovascular Research Foundation, New York, New York.

Abstract

We report the case of an 81-year-old woman with symptomatic severe aortic stenosis, extremely significant peripheral arterial disease, and obstructive coronary artery disease who underwent percutaneous coronary intervention via a transaxillary conduit immediately before a trans-apical transcatheter aortic valve replacement performed with a transfemoral device. After deployment of the transcatheter heart valve, there was a left main coronary obstruction and the patient required an emergent PCI. This multifaceted case clearly underlines the importance of a well functioning heart team including the interventional cardiologist, the cardiovascular surgeon, and the echocardiographer. © 2013 Wiley Periodicals, Inc.

PMID: 23413172

Transapical deployment of an Aortic Valve

WATCH VIDEO

Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment

This is an interesting surgical case presented by the Columbia University Cardiovascular Surgery team, illustrating the importance of combined team skills in the most difficult of cases. It is part of a series on cardiovascular surgery.

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Paradis JM, George I, and Kodali S

Catheterization and Cardiovascular Interventions (2013)

http://dx.doi.org/10.1002/ccd.24865

Introduction

Transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN transcatheter heart valve (THV) (Edwards Lifesciences, Irvin, CA) has been shown to reduce mortality when compared to medical therapy alone for patients with symptomatic severe aortic stenosis deemed unsuitable for surgical aortic valve replacement due to multiple co-morbidities. The Edwards SAPIEN THV, sizes 23 and 26 mm, and the RetroFlex 3 transfemoral delivery system, have been recently approved by the US Food and Drug Administration (FDA) for commercial use outside of the PARTNER clinical trial for patients considered inoperable. However, an alternative site needs to be selected for patients with peripheral arteries inadequate for transfemoral TAVR. Although not fully validated, the transapical approach or the transaortic route using a balloon expandable THV, appears to be appropriate for this specific purpose. Significant coronary artery disease (CAD) is often found in patients with severe aortic stenosis. in > 50% of patients with aortic stenosis over 70 years of age and in > 65% of patients who are over 80 years of age. There is no established guideline for managing significant CAD in the context of TAVR, including the appropriate revascularization strategy as well as the timing of interventions.

Case Report

An 81-year-old woman presented with symptomatic severe aortic stenosis, extremely significant peripheral arterial disease, and obstructive coronary artery disease. She had a six-month history prior to admission of progressive exertional shortness of breath and fatigue, and a long history fo hypertension, hyperlipidemia, obesity, and severe peripheral vascular disease. In 2003, she underwent a coronary artery bypass graft (CABG) surgery, with grafting of the left internal mammary artery (LIMA) to the left anterior descending (LAD) artery, a saphenous vein graft (SVG) to the first obtuse marginal (OM) branch, and a SVG to the right coronary artery (RCA). Due to associated severe mitral regurgitation, a mitral valve ring annuloplasty was also performed. A transthoracic echocardiogram (TTE) revealed severe aortic stenosis with a peak gradient across the aortic valve of 63 mm Hg, a mean gradient of 39 mm Hg, and an aortic valve area of 0.8 cm2. The left ventricular ejection fraction (LVEF) was 64% while the pulmonary artery systolic pressure was measured at 28 mm Hg. Extreme calcification and tortuosity precluded the advancement of any wire, catheter, or sheath, contributing to two attempts at cardiac catheterization prior to transfer with a total occlusion of the distal abdominal aorta, at the level of the aorto-iliac bifurcation, and the left main, proximal LAD, proximal left circumflex, and the proximal RCA all had greater than 70% coronary lesions. In addition, ostial total occlusions were seen in both SVGs.

After transfer, a cardiac catheterization through the right radial artery was attempted without success due to calcification and tortuosity in the arterial bed. An 80% distal left main lesion was clearly identified with a Judkins left 3.5 guiding catheter. There was non-flow limiting coronary disease in the left circumflex and competitive retrograde flow seen in the LIMA graft, but they still were unable to cannulate the RCA and the SVGs. It was determined that the patient was inoperable, on grounds of her significant frailty, reoperative status and overall comorbid state (Society of Thoracic Surgeons (STS) risk score of 11%). Furthermore, due to the occlusion of the distal aorta, the patient was unsuitable for a TAVR via the transfemoral approach.

They chose to approach her PCI via a conduit on the right axillary artery and perform a concomitant TAVR from a trans-apical approach due to the serious limiting condition of the patient. She underwent percutaneous coronary intervention via a transaxillary conduit immediately before a trans-apical transcatheter aortic valve replacement performed with a transfemoral device. Excellent flow from the conduit was noted. A 7 French (Fr) sheath was connected to the end of the conduit, which was kept long to allow better maneuverability (Fig. 1). A Rosen wire was passed with some difficulty to the aortic root, and was switched to a stiff wire in an attempt to straighten the vessel.

Fig. 1. Transaxillary conduit used during the procedure. A 7 French sheath was connected to an 8 mm dacron graft, which was previously sewn to the axillary artery.

After deployment of the transcatheter heart valve, there was a left main coronary obstruction and the patient required an emergent PCI. This multifaceted case clearly underlines the importance of a well functioning heart team including the interventional cardiologist, the cardiovascular surgeon, and the echocardiographer. A Xience

V everolimus eluting stent 3.5 mm 18 mm was implanted starting 2 mm distal to the ostium of the left main, extending in the proximal portion of the left circumflex artery. After one post-dilatation with a non-compliant balloon, the final angiographic result was excellent.

They used a Retroflex 3 transfemoral delivery sheath to perform the trans-apical TAVR. They estimated the size and length of the ventricular cavity, and then placed markers on the delivery sheath (prior to insertion) indicating the appropriate length of sheath to remain outside the heart (Fig. 2).

Fig. 2. Marker placed on the RetroFlex 3 transfemoral sheath to safely guide its insertion inside the left ventricular cavity during the trans-apical transcatheter aortic valve replacement.

A 23 mm Edwards SAPIEN valve was selected and deployed under fluoroscopic and transesophageal echocardiographic guidance. Immediately after deployment, turbulent flow was noted within the left main with the color Doppler on TEE, indicating a new obstruction of the left main, which a left coronary angiogram showed to be a severe proximal lesion. Through the trans-axillary conduit, a guiding catheter was laboriously brought in the ascending aorta and cannulated the left main artery which permitted a predilation and a stent insertion in the ostial portion of the left main. She was discharged to a rehabilitation facility 7 days after the procedure.

On follow-up TTE, the LVEF was 55% without any significant wall motion abnormality. There was no aortic regurgitation, and the peak and mean gradients were 14.9 mm Hg and 8.0 mm Hg, respectively. The patient is still doing well more than 6 months after the procedure. She is now in NYHA class 2 and has not had any recurrent hospitalization for congestive heart failure.

Discussion

This report is a case of a complex percutaneous coronary intervention of the left main coronary artery via a right axillary conduit followed immediately by an off label commercial transapical TAVR using the Retro-Flex 3 trans-femoral introducer sheath, complicated finally by a new left main coronary obstruction mandating another PCI. It is the first description of a TAVR procedure preceded and followed by a left main trans-axillary PCI. The role of TEE (color Doppler) in the diagnosis of a very rare TAVR complication is also noteworthy. In a recent meta-analysis of 3,519 patients from 16 studies using the Valve Academic Research Consortium (VARC) definitions, the pooled estimate rate of coronary

obstruction following TAVR was only 0.7%. Obviously, the early recognition and treatment of this hazard is imperative.

The surgical management of this patient also warrants discussion. The hybrid surgical approach of accessing the axillary artery via a conduit provides numerous advantages:

(1) the ascending aorta, coronaries, and aortic valve are easily accessible;

(2) transition to cardiopulmonary bypass or extra-corporeal membrane oxygenation, if needed, is quick; and

(3) long-term morbidity is minimal for the patient when compared to aorto-iliac, aortic, or femoral conduits.

Finally, the heart team approach not only allowed the realization of a difficult coronary

stent implantation through an unusual transaxillary graft followed by a transapical TAVR in a patient with significant peripheral arterial disease, but also permitted the early recognition and management of a potentially fatal left main obstruction. Considerations such as team-based care, close communication between the different specialties

involved and careful planning for outlining management of potential complications are therefore essential for the success of a TAVR program.

REFERENCES

1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–1607.

2. Iung B. Interface between valve disease and ischaemic heart disease. Heart 2000;84:347–352.

3. Wenaweser P, Pilgrim T, Guerios E, Stortecky S, Huber C, Khattab AA, et al. Impact of coronary artery disease and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation.

EuroIntervention 2011;7:541–548.

4. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, et al. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: A weighted meta-analysis of 3,519 patients from 16 studies.

J Am Coll Cardiol 2012;59:2317–2326.

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Three coronary artery bypass grafts, a LIMA to LAD and two saphenous vein grafts – one to the right coronary artery (RCA) system and one to the obtuse marginal (OM) system. (Photo credit: Wikipedia)

heart with coronary arteries (Photo credit: Wikipedia)

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Frontiers in Cardiology and Cardiovascular Disorders, Valves & Tools, tagged Aortic insufficiency, Aortic valve, Aortic valve replacement, Columbia University, Columbia University Medical Center, Doctor of Philosophy, Edwards Lifescience, surgery, TAVR on June 17, 2013| 8 Comments »

Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

Reviewer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This report is one in a series on advances in cardiovascular surgery. This report particularly focuses on the safety and efficacy of transcatheter aortic valve replacement (TAVR), a major study carried out at Columbia University Medical Center, involving reduction of paravalvular regurgitation post TAVI.

Circ Cardiovasc Interv. 2013 Feb;6(1):85-91. doi: 10.1161/CIRCINTERVENTIONS.112.971614. Epub 2013 Jan 22.

Efficacy and safety of postdilatation to reduce paravalvular regurgitation during balloon-expandable transcatheter aortic valve replacement.

Daneault B, Koss E, Hahn RT, Kodali S, Williams MR, Généreux P, Paradis JM, George I, Reiss GR, Moses JW, Smith CR, Leon MB.

Source

Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, NY 10032, USA.

Abstract

BACKGROUND:

Paravalvular regurgitation (PVR) is common after transcatheter aortic valve replacement (TAVR) and may be associated with adverse outcomes. Postdilatation (PD) has been proposed to treat PVR without being formally studied. We performed a study to evaluate the safety and efficacy of PD after balloon expandable TAVR.

METHODS AND RESULTS:

Consecutive cases of TAVR were reviewed for clinical outcomes. Procedural transesophageal echocardiography imaging was reviewed for a subgroup of consecutive patients. PVR areas seen on a short-axis view were measured immediately after deployment, after PD, and at the completion of the study. Stent dimensions measured using angiography and the Paieon’s C-THV system pre- and post-PD were compared. Between May 2007 and November 2011, 259 patients underwent TAVR at our institution. PD was performed in 106 patients (41%). These patients had larger annulus, lower cover-index; more often had transfemoral access and implantation of a 26 mm valve. There was a nonsignificant greater rate of cerebrovascular events in PD patients. There was no significant difference in major aortic injury and permanent pacemaker implantation rates between groups. TTE studies were reviewed in 58 patients (35 with PD and 23 without PD). PD patients had larger PVR areas immediately after deployment (40.3±17.1 versus 15.4±14.2 mm(2); P<0.0001). There was significant reduction in PVR area attributable to PD (21.7±9.3 mm(2); P<0.0001). Spontaneous regression of PVR was seen in both groups. PD increased stent dimensions.

CONCLUSIONS:

This study demonstrates the efficacy of PD at reducing PVR in patients with greater than mild PVR after balloon-expandable TAVR.

PMID: 23339841

Efficacy and Safety of Postdilatation to Reduce Paravalvular Regurgitation During Balloon-Expandable Transcatheter Aortic Valve Replacement

Daneault R, Koss E, Hahn RT, Kodali S, Williams MR, et al.
Circ Cardiovasc Interv. 2013;6:85-91. http://dx.doi.org/10.1161/circinterventions.112.971614

Transcatheter aortic valve replacement (TAVR) has emerged as a new alternative treatment for patients with severe aortic stenosis, who are at high risk or deemed inadequate candidates for conventional surgical aortic valve replacement. Paravalvular regurgitation (PVR) is common after transcatheter aortic valve replacement (TAVR) reported in 80% to 96% of TAVR cases Moreover, moderate and severe degrees of regurgitation are associated with worse clinical outcomes While the risk factors are known and include: smaller cover index, annulus eccentricity, and the degree and distribution of leaflet calcifications, postdilatation (PD) of balloon expandable valves after implantation, including transcatheter heart valve (THV) traumatic aorta injury, cerebrovascular embolus, and conduction block may outweigh the potential benefits from reduction in aortic regurgitation. Therefore, these investigators performed a study to evaluate the safety and efficacy of PD after balloon expandable TAVR.

What Is Known

• Significant paravalvular regurgitation after transcatheter aortic valve replacement is associatedwith increased mortality.
• Calcifications, undersized prosthesis, and malposition are causes of paravalvular regurgitation.

Study Design

Procedural and in-hospital outcomes for all consecutive patients treated between May 2007 and November 2011 with Edwards SAPIEN THV (Edwards Lifescience, Irvine, CA) as part of the PARTNER and PARTNER 2 trials were reviewed both prospectively and retrospectively. Information on PD was collected retrospectively from chart and imaging review for the period between 2007 and August 2010, and prospectively after August 2010. PD was performed in cases where PVR was qualitatively more than mild, by transesophageal echocardiography (TEE), immediately after THV implantation. There were 259 patients who underwent TAVR. PD was performed in 106 patients (41%). Procedural transesophageal echocardiography imaging was reviewed for a subgroup of consecutive patients. PVR areas seen on a short-axis view were measured immediately after deployment, after PD, and at the completion of the study. Stent dimensions measured using angiography and the Paieon’s C-THV system pre- and post-PD were compared, and TTE studies were reviewed in 58 patients (35 with PD and 23 without PD).

Endpoints

Neurological events were defined using valve academic research consortium definitions.14 Cover-index is defined as: 100×([THV diameter–TEE annulus diameter]/THV diameter).3 Clinical end points for the current analysis included 30-day mortality, in-hospital stroke or transient ischemic attack, procedural related major aortic injury (aortic dissection, aortic wall hematoma, or annulus/aortic rupture) and need for new permanent pacemaker during the index hospitalization. Echocardiographic end points included spontaneous reduction of PVR [difference between PVR1 and PVR3 in the non-PD group (PD−) and difference between PVR2 and PVR3 in the PD group (PD+)], and reduction of PVR attributable to PD
(PVR1−PVR2) in the PD+. Angiographic end points included additional expansion of IF, OF, and minimal diameters of stents after PD.

Results and Clinical Outcomes

No valve embolization occurred during PD. No patient required implantation of a second THV after PD. Multiple PD was performed in 4 cases. There was no statistically significant
difference between the 2 groups in the incidence of neurological events, although they were more frequent in patients with PD. Permanent pacemaker implantation during the index hospitalization was not significantly different between the 2 groups. Major aortic injuries were rare and occurred at a similar rate between both groups with no aortic annulus rupture in either group.

These (PD) patients had larger annulus, lower cover-index; more often had transfemoral access and implantation of a 26 mm valve. There was a nonsignificant greater rate of cerebrovascular events in PD patients. There was no significant difference in major aortic injury and permanent pacemaker implantation rates between groups.
PD patients had larger PVR areas immediately after deployment (40.3±17.1 versus 15.4±14.2 mm2; P<0.0001). There was significant reduction in PVR area attributable to PD (21.7±9.3 mm2; P<0.0001). Spontaneous regression of PVR was seen in both groups.
PD increased stent dimensions. There was a significant increase in the OF, IF, and minimal diameters after PD of 26 mm valves. The changes were not statistically significant for the 23 mm valves. There was a greater expansion in the IF and OF diameters compared with the minimal diameter.

Discussion

This study is the second that demonstrates the efficacy of PD at reducing postdeployment PVR in patients with greater than mild PVR after balloon-expandable TAVR. Moreover, judicious use of PD for greater than mild PVR is not associated with excess morbidity or mortality, although some concerns regarding cerebral embolism deserve comment. When it occurs, PVR is a significant cause of nonstructural prosthetic valve dysfunction. The anatomic positioning and resultant physiology of THV, however, are different from surgical valves. After surgical aortic valve replacement, most commonly PVR is attributable to infection, suture dehiscence, or fibrosis and calcification of the native annulus, resulting in inadequate contact or gaps between the sewing ring and annulus. Because THVs do not have a sewing ring traditional dehiscence cannot occur. For balloon-expandable THV, significant PVR most commonly results from incomplete prosthesis apposition to the native annulus.

What the Study Adds

• Additional postdilatation can reduce the magnitude of paravalvular regurgitation.
• Spontaneous regression of paravalvular regurgitation occurs within minutes after transcatheter aortic valve replacement.
• Postdilatation may be associated with increased risk of cerebrovascular events.

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Harnessing New Players in Atherosclerosis to Treat Heart Disease

Posted in Atherogenic Processes & Pathology, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Resident-cell-based, tagged Columbia University Medical Center, Harvard Medical School, New York Academy of Sciences, Washington University School of Medicine on April 25, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Harnessing New Players in Atherosclerosis to Treat Heart Disease

Tuesday, September 24, 2013 | 8:30 AM – 4:30 PM

The New York Academy of Sciences

Presented by the Biochemical Pharmacology Discussion Group

Atherosclerosis is defined as a chronic inflammatory disease affecting arterial blood vessels involving dysregulation of the endothelial-leukocyte adhesive interactions, increased leukocyte apoptosis within the plaque, and defective phagocytosis of apoptotic cells. Despite the key role of monocytes/macrophages in atherosclerosis, mounting evidence suggests that dysregulation of other cell types may be independent risk factors for atherosclerosis. Leukocytes are produced daily and are derived from hematopoietic stem and progenitor cells within the bone marrow in a process call hematopoiesis. A better understanding of this process will open an avenue to identify new targets to fight atherosclerosis.

*Reception to follow.

Organizers

Mercedes Beyna, MS

Pfizer Global Research and Development

Nadeem Sarwar, PhD

Pfizer Global Research and Development

Laurent Yvan-Charvet, PhD

INSERM U1065/UNS, C3M

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Matthias Nahrendorf, MD, PhD

Harvard Medical School

Alan R. Tall, MD, PhD

Columbia University Medical Center

http://www.nyas.org/Events/Detail.aspx?cid=1103f191-2d94-4f37-b91f-64293dc88019

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The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, tagged ACS, Columbia University Medical Center, Harvard Medical School, myocardial infarction, ST elevation, TIMI on January 3, 2013| 17 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Acute Coronary Syndrome

Tool Identifies Risk in Stenting ACS Patients

By Todd Neale, Senior Staff Writer, MedPage Today

Published: November 19, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new, easy-to-calculate risk score developed for patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) had better prognostic accuracy than other widely used risk scores, researchers found.

The ACUITY-PCI risk score includes six variables — insulin-treated diabetes, renal insufficiency, baseline cardiac biomarker elevation or ST-segment deviation, presence of a bifurcation lesion, small vessel/diffuse coronary artery disease, and extent of coronary artery disease, according to Gregg Stone, MD, of Columbia University Medical Center in New York City, and colleagues.

The 1-year rate of death or MI significantly increased from 5.3% in the lowest risk tertile to 9.1% in the middle tertile to 19% in the highest tertile (P<0.001), the researchers reported in the November issue of JACC: Cardiovascular Interventions.

Discrimination and calibration were greater with the ACUITY-PCI score than with other established scores.

“Although the TIMI and the GRACE scores have been shown to be valuable prognostic tools at the time of hospital admission for selecting pharmacological strategies and identifying those patients most likely to benefit from an invasive strategy, they have not been optimized for patients undergoing PCI and, thus, have relatively poor prognostic power to further risk stratify acute coronary syndrome patients undergoing PCI,” Stone and colleagues wrote.

“The ACUITY-PCI score is therefore intended to supplement the TIMI and GRACE scores when an invasive strategy has been undertaken and PCI is being considered.”

The researchers created the risk score using data from 1,692 patients enrolled in the angiographic substudy of the ACUITY trial, which was a comparison of heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin (Angiomax) plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone in patients with ACS undergoing an early invasive strategy. They then validated the score using another 846 patients from the same study.

Multivariate analysis revealed six variables that were significantly associated with 1-year mortality and MI and were included in the score. The researchers assigned points based on the strength of the predictor:

Insulin-treated diabetes (12 points)
Renal insufficiency (12 points)
Baseline cardiac biomarker elevation or ST-segment deviation (8 points)
Bifurcation lesion (4 points)
Small vessel/diffuse coronary artery disease (2 points)
Extent of coronary artery disease (1 point for each 10 mm of disease)

The C-statistic for the risk score — a measure of discrimination — was 0.67 in the derivation cohort and 0.70 in the validation cohort. In the validation cohort, the chi-square statistic for calibration was 6.2 and the index of separation was 0.44.

All of those values were better than those seen for four other established risk scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX. In addition, the net reclassification improvement with the new score ranged from 9% to 38% and the integrated discrimination index varied from 1.9% to 2.7%.

The researchers noted that the ACUITY-PCI score also was a good predictor of 1-year definite or probable stent thrombosis, with a C-statistic of 0.72.

In another study in the same journal, George Dangas, MD, PhD, of Mount Sinai Medical Center in New York City, and colleagues — including Stone — reported on the development of a risk score specifically for stent thrombosis in patients with ACS undergoing PCI.

The study included 6,139 patients from the HORIZONS-AMI and ACUITY trials, which included those with ST-segment elevation MI (STEMI) in the former trial and those with non-STEMI and unstable angina in the latter. The researchers used 4,093 patients for the derivation cohort and 2,046 for the validation cohort.

The risk score included 10 variables that were significantly associated with the risk of Academic Research Consortium-defined definite or probable stent thrombosis at 1 year:

Type of acute coronary syndrome (4 points for STEMI, 2 points for non-ST-segment elevation ACS with ST deviation, and 1 point for non-ST-segment elevation ACS without ST changes)
Current smoking (1 point)
Insulin-dependent diabetes (2 points)
Prior PCI (1 point)
Baseline platelet count (1 point for 250 to 400 K/µL and 2 points for more than 400 K/µL)
Absence of pre-PCI heparin therapy (1 point)
Aneurysmal/ulcerated lesion (2 points)
Baseline TIMI flow grade 0/1 (1 point)
Final TIMI flow grade less than 3 (1 point)
Number of treated vessels (1 point for two vessels and 2 points for three vessels)

Scores from 1 to 6 are considered low risk, 7 to 9 are intermediate risk, and 10 or higher are high risk.

The rates of stent thrombosis at 1 year were 1.36%, 3.06%, and 9.18% across the three risk tertiles in the derivation cohort (P<0.001 for trend), with a similar trend seen in the validation cohort.

The C-statistics were 0.67 in the derivation cohort and 0.66 in the validation cohort. Performance was comparable for events occurring both early (within the first 30 days) and late (from 1 month to 1 year).

“We believe that the development and initial validation of this stent thrombosis risk score can be a useful tool for both clinical practice and future clinical investigation (future analyses of trials or registries), as it can be a simple way to risk stratify patients immediately following a procedure,” Dangas and colleagues wrote. “The risk score could also be used in the informed consent process to better inform patients of their individual risk of stent thrombosis.”

But Ron Waksman, MD, and Israel Barbash, MD, of MedStar Washington Hospital Center in Washington, D.C., noted some limitations of the tool, including the pooling of different types of patients, the exclusion of important variables associated with stent thrombosis risk, and the use of mostly first-generation drug-eluting stents in the trials.

“It is imperative that the user of such a prediction tool be aware of its capabilities and performance, as well as its limitations, in various clinical scenarios,” they wrote in an accompanying editorial.

“A newly developed risk score for stent thrombosis should be robust and should be tested across broad study populations, stents, and antiplatelet regimens. A new model should also be validated in a setting different from the one in which it was derived,” they wrote. “Unfortunately, this is not the case with the newly proposed model.”

“Until such an encompassing tool is developed and validated,” they wrote, “one should rely on the known stent thrombosis risk factors and tailor an appropriate treatment for each patient.”

The ACUITY trial was funded by The Medicines Company and Nycomed.

Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, and The Medicines Company. His co-authors reported relationships with Abbott, Regado, Ortho McNeil, Janssen, Merck, Maya Medical, AstraZeneca, Sanofi/Bristol-Myers Squibb, Eli Lilly, and Daiichi Sankyo.

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and The Medicines Company.

Dangas has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, The Medicines Company, sanofi-aventis, and Abbott Vascular. His co-authors reported relationships with sanofi-aventis, The Medicines Company, Abbott Vascular, Bristol-Myers Squibb, Cordis, AstraZeneca, Daiichi Sankyo, Eli Lilly, Maquet, Roche, Boehringer Ingelheim, Liposcience, Merck, Pozen, Gilead Sciences, WebMD, the NIH, Pfizer, Johnson & Johnson, Schering-Plough, Merck Sharpe and Dohme, GlaxoSmithKline, Regado Biosciences, Boston Scientific, and Bristol-Myers Squibb/Sanofi.

Waksman and Barbash reported that they had no conflicts of interest.

From the American Heart Association:

2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

Primary source: JACC: Cardiovascular Interventions
Source reference:
Palmerini T, et al “A new score for risk stratification of patients with acute coronary syndromes undergoing percutaneous coronary intervention: the ACUITY-PCI (Acute Catheterization and Urgent Intervention Triage Strategy-Percutaneous Coronary Intervention) risk score” JACC Cardiovasc Interv 2012; 5: 1108-1116.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Dangas G, et al “Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes” JACC Cardiovasc Interv 2012; 5: 1097-1105.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Waksman R, Barbash I “The appropriate use of risk scores” JACC Cardiovasc Interv 2012; 5: 1106-1107.

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University. He is based atMedPage Today headquarters in Little Falls, N.J.

SOURCE:

http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/36010

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Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Bio Instrumentation in Experimental Life Sciences Research, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, Valves & Tools, tagged Aortic valve, Aviva Lev-Ari, Columbia University Medical Center, Edward Lifescience, Percutaneous aortic valve replacement, TAVR, Transcatheter Aortic Valve Implantation on September 3, 2012| 4 Comments »

Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Reporter: Aviva Lev-Ari, PhD, RN

Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Raj R. Makkar, M.D., Gregory P. Fontana, M.D., Hasan Jilaihawi, M.D., Samir Kapadia, M.D., Augusto D. Pichard, M.D., Pamela S. Douglas, M.D., Vinod H. Thourani, M.D., Vasilis C. Babaliaros, M.D., John G. Webb, M.D., Howard C. Herrmann, M.D., Joseph E. Bavaria, M.D., Susheel Kodali, M.D., David L. Brown, M.D., Bruce Bowers, M.D., Todd M. Dewey, M.D., Lars G. Svensson, M.D., Ph.D., Murat Tuzcu, M.D., Jeffrey W. Moses, M.D., Matthew R. Williams, M.D., Robert J. Siegel, M.D., Jodi J. Akin, M.S., William N. Anderson, Ph.D., Stuart Pocock, Ph.D., Craig R. Smith, M.D., and Martin B. Leon, M.D. for the PARTNER Trial Investigators

N Engl J Med 2012; 366:1696-1704 May 3, 2012

Background

Transcatheter aortic-valve replacement (TAVR) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The outcomes beyond 1 year in such patients are not known.

Methods

We randomly assigned patients to transfemoral TAVR or to standard therapy (which often included balloon aortic valvuloplasty). Data on 2-year outcomes were analyzed.

Results

A total of 358 patients underwent randomization at 21 centers. The rates of death at 2 years were 43.3% in the TAVR group and 68.0% in the standard-therapy group (P<0.001), and the corresponding rates of cardiac death were 31.0% and 62.4% (P<0.001). The survival advantage associated with TAVR that was seen at 1 year remained significant among patients who survived beyond the first year (hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.92; P=0.02 with the use of the log-rank test). The rate of stroke was higher after TAVR than with standard therapy (13.8% vs. 5.5%, P=0.01), owing, in the first 30 days, to the occurrence of more ischemic events in the TAVR group (6.7% vs. 1.7%, P=0.02) and, beyond 30 days, to the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, P=0.16). At 2 years, the rate of rehospitalization was 35.0% in the TAVR group and 72.5% in the standard-therapy group (P<0.001). TAVR, as compared with standard therapy, was also associated with improved functional status (P<0.001). The data suggest that the mortality benefit after TAVR may be limited to patients who do not have extensive coexisting conditions. Echocardiographic analysis showed a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of paravalvular aortic regurgitation.

Conclusions

Among appropriately selected patients with severe aortic stenosis who were not suitable candidates for surgery, TAVR reduced the rates of death and hospitalization, with a decrease in symptoms and an improvement in valve hemodynamics that were sustained at 2 years of follow-up. The presence of extensive coexisting conditions may attenuate the survival benefit of TAVR. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)

Supported by Edwards Lifesciences.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMoa1202277) was published on March 26, 2012, and updated on August 30, 2012, at NEJM.org.

Source Information

From Cedars–Sinai Heart Institute, Los Angeles (R.R.M., H.J., R.J.S.); Lenox Hill Heart and Vascular Institute (G.P.F.) and Columbia University Medical Center and New York Presbyterian Hospital (S. Kodali, J.W.M., M.R.W., C.R.S., M.B.L.) — both in New York; Cleveland Clinic Foundation, Cleveland (S. Kapadia, L.G.S., M.T.); Washington Hospital Center, Washington, DC (A.D.P.); Duke University School of Medicine, Durham, NC (P.S.D.); Emory University School of Medicine, Atlanta (V.H.T., V.C.B.), University of British Columbia and St. Paul’s Hospital, Vancouver, Canada (J.G.W.); Hospital of the University of Pennsylvania, Philadelphia (H.C.H., J.E.B.); Baylor Healthcare System (D.L.B., B.B.) and Medical City Dallas (T.M.D.) — both in Dallas; Edwards Lifesciences, Irvine, CA (J.J.A., W.N.A.); and London School of Hygiene and Tropical Medicine, London (S.P.).

Address reprint requests to Dr. Leon at Columbia University Medical Center, Center for Interventional Vascular Therapy, 161 Fort Washington Ave., 6th Fl., New York, NY 10032, or at mleon@crf.org.

The investigators, institutions, and research organizations participating in the Placement of Aortic Transcatheter Valves (PARTNERS) trial are listed in the Supplementary Appendix, available at NEJM.org.

http://www.nejm.org/doi/full/10.1056/nejmoa1202277

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Cardiology, Cardiovascular disease, Columbia University Medical Center, Craig Smith, Eugene Braunwald, Implantable Synchronized Cardiac Assist Device, New England Journal of Medicine, Triple Antihypertensive Combination Therapy on August 17, 2012| 8 Comments »

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Reported: Aviva Lev-Ari, PhD, RN

UPDATED on 11/22/2018 – Published Activity on http://pharmaceuticalintelligence.com

World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

(a) Real Time Highlights and Tweets: Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/03/deliverables-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-httpsworldmedicalinnovation-orgagenda-highlights-of-live-day-1-world-medical/

(b) e-Proceedings for Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/05/e-proceedings-for-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

(c) Tweets by @pharma_BI and @AVIVA1950 at World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/05/tweets-by-pharma_bi-and-aviva1950-at-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

UPDATED on 11/22/2018 – External Sources

Latest Medical Devices, Equipment, & Drug Information in Cardiology

Search the latest Cardiology developments in medical devices, equipment and approved drugs. Find new FDA approved procedures, drugs and devices in the MDLinx Product Center.

https://www.mdlinx.com/cardiology/product-center/

5 New Implantable Cardiovascular Technologies to Watch

Recent device technology advances may offer new therapies for atrial fibrillation and heart failure

https://www.dicardiology.com/article/5-new-implantable-cardiovascular-technologies-watch

Advances and Trends in Vascular Closure Devices

Faster hemostasis saves nursing time, speeds patient ambulation

https://www.dicardiology.com/article/advances-and-trends-vascular-closure-devices

Drivers and Trends in Cardiovascular Device Development: Insights from Key Opinion Leaders

Medical Device Clinical Trials, Medical Device Design, Medical Device Manufacturing & Supply Chain, Medical Device Safety and Regulation

https://xtalks.com/webinars/cardiovascular-device-development-insights-from-key-opinion-leaders/

Cardiology Industry 2018

View Trends, Analysis and Statistics.

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SOURCE

https://www.reportlinker.com/market-report/Health-Services/115531/Cardiology?utm_source=bingads_usa&utm_medium=cpc&utm_campaign=Healthcare&utm_adgroup=Cardiology_Trends&msclkid=8801b5a8be3910db0eaaee5e55981f3e&utm_term=%2Bcardiology%20%2Btrends&utm_content=Cardiology%20Trends

2012

Dr. Joseph Loscalzo of BWH, the moderator of the Cardiology Panel — NEJM Dialogue in Medicine, June 22, 2012 has asked the Panel members: What are the new innovations to be foreseen by each member of the Panel which included Panelists:

Emelia Benjamin, BMC

Eugene Braunwald, BWH,

Desmond Jordan, Columbia University Medical Center

Thomas Luscher, Professor and Chairman of Cardiology at the University Hospital Zurich and Director of CardioVascular Research at the Institute of Physiology of the University Zurich, Switzerland.

Craig Smith, Columbia University Medical Center

Dr. Craig Smith of Columbia University Medical Center bet the future of cardiovascular medical devices on the Implantable Synchronized Cardiac Assist Device which has three version, Left ventricle, Right Ventricle or both

Dr. Eugene Braunwald, Founding Chairman, TIMI Study Group (TIMI stands for ‘Thrombolysis In Myocardial Infarction’ and is the name of an Academic Research Organization (ARO) that, since it was founded by Dr. Eugene Braunwald in 1984, has conducted numerous practice-changing clinical trials in patients with cardiovascular disease or risk factors for cardiovascular disease, he has expressed anticipation of the next big and much needed to be available — the Multiple Pill, one drug that is a combination drugs of ASA, TZD, BB, ACE, Statin.

On this Scientific Web Site — Frontiers in Cardiology is one of the Research Categories on Cardiovascular disease, research directed by Dr. Aviva Lev-Ari, noted to be of great relevance to the innovations foreseen by Dr. Craig Smith and by Dr. Brounwald, as expressed by them on June 22, 2012 in Boston, MA

To read on Implantable Artificial Heart — go to

Lev-Ari, A. (2012G). Heart Remodeling by Design: Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

To read on the only currently available Multiple Pill — go to

Lev-Ari, A. (2012b). Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

http://pharmaceuticalintelligence.com/2012/05/29/445/

To watch the video of the Cardiology Panel — go to

http://nejm200.nejm.org/news-and-events/dialogues-in-medicine/?panel=4

To review our post on the Cardiology Panel — go to

http://pharmaceuticalintelligence.com/2012/08/16/cardiology-panel-nejm-dialogue-in-medicine-june-22-2012/

To review TIMI research results — go to

http://www.timi.org/

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Children Exposed to the Common Pollutant Naphthalene Show Signs of Chromosomal Damage

Posted in Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged American Association for Cancer Research, Centers for Disease Control and Prevention, Columbia Mailman School of Public Health, Columbia University Medical Center, Morgan Stanley Children's Hospital, Professional degrees of public health on May 30, 2012| 1 Comment »

Reporter: Prabodh Kandala, PhD

According to a new study, children exposed to high levels of the common air pollutant naphthalene are at increased risk for chromosomal aberrations (CAs), which have been previously associated with cancer. These include chromosomal translocations, a potentially more harmful and long-lasting subtype of CAs.

Researchers from the Columbia Center for Children’s Environmental Health (CCCEH) at the Mailman School of Public Health, Columbia University Medical Center, and the Centers for Disease Control and Prevention (CDC) report the new findings in Cancer, Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Naphthalene is found in both outdoor and indoor urban air. It is present in automotive exhaust, tobacco smoke, and is the primary component of household mothball fumes. Classified as a possible carcinogen by the International Agency for Cancer Research, naphthalene belongs to a class of air pollutants called polycyclic aromatic hydrocarbons (PAH). Prior research at the CCCEH has established a link between prenatal exposure to PAH and increased risk for childhood obesity, IQ deficits, and CAs. The new study is the first to present evidence in humans of CAs, including translocations, associated with exposure to one specific PAH — naphthalene — during childhood.

The researchers followed 113 children, age 5, who are part of a larger cohort study in New York City. They assessed the children’s exposure to naphthalene; a CDC laboratory measured levels of its metabolites — 1- and 2-naphthol — in urine samples. (Metabolites are products of the body’s metabolism, and can serve as marker for the presence of a chemical.) Researchers also measured CAs in the children’s white blood cells using a technique called fluorescent in situ hybridization. Chromosomal aberrations were present in 30 children; of these, 11 had translocations. With every doubling of levels of 1- and 2-naphthol, translocations were 1.55 and 1.92 times more likely, respectively, to occur.

CAs have been associated with increased cancer risk in adults. Translocations are of special concern as they result in a portion of one chromosome being juxtaposed to a portion of another chromosome, potentially scrambling the genetic script. “Translocations can persist for years after exposure. Some accumulated damage will be repaired, but not everyone’s repair capacity is the same. Previous studies have suggested that chromosomal breaks can double an adult’s lifetime risk for cancer, though implications for children are unknown,” says first author Manuela A. Orjuela, MD, ScM, assistant professor of clinical environmental health sciences and pediatrics (oncology) at Columbia University Medical Center and a pediatric oncologist at NewYork-Presbyterian Morgan Stanley Children’s Hospital.

To obtain a better sense of the long-term consequences of naphthalene exposure, Dr. Orjuela and other CCCEH investigators are following some of the children in the study as they reach fourth grade. While they expect to see further translocations, they do not expect to see any signs of cancer in the white blood cells. “So far, the translocations seem to be random, and there has been no evidence of the specific translocations that are known to be associated with leukemia. This is entirely expected; leukemia is very rare.” Frederica Perera, DrPH, senior author on the paper, adds that “the findings provide yet more evidence of the vulnerability of the young child to carcinogenic air pollutants.”

The researchers hypothesized that naphthalene exposure was primarily from mothballs, which can release high levels of the chemical. Furthermore, according to previous research, some Caribbean immigrant families use mothballs as an air freshener. Other important sources of naphthalene in indoor air are tobacco smoke, paint fumes, cooking, and heating. The new findings have implications beyond the urban environment as elevated levels of naphthalene metabolites have been documented in rural communities using biomass-burning stoves (coal, wood) — another source of PAH exposure.

Ref:

http://www.sciencedaily.com/releases/2012/05/120529113635.htm

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Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com

Posts Tagged ‘Columbia University Medical Center’

Systems Biology analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

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Real Time Coverage @BIOConvention #BIO2019: Keynote: Siddhartha Mukherjee, Oncologist and Pulitzer Author; June 4 9AM Philadelphia PA

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Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

A stepwise progression in the treatment of cardiogenic shock.

Pollack A, Uriel N, George I, Kodali S, Takayama H, Naka Y, Jorde U.

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Care of the Critically Ill: A Stepwise Progression in the Treatment of Cardiogenic Shock.

Initial Presentation

Transfer to NY Presbyteran Columbia Hospital

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Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

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Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Introduction

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Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

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Efficacy and Safety of Postdilatation to Reduce Paravalvular Regurgitation During Balloon-Expandable Transcatheter Aortic Valve Replacement

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Harnessing New Players in Atherosclerosis to Treat Heart Disease

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Mercedes Beyna, MS

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Matthias Nahrendorf, MD, PhD

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Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Background