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Taylor C.A.,HeartFlow | Taylor C.A.,Stanford University | Fonte T.A.,HeartFlow | Min J.K.,Cedars Sinai Heart Institute
Journal of the American College of Cardiology | Year: 2013

Coronary computed tomography angiography (CTA) has emerged as a noninvasive method for direct visualization of coronary artery disease, with previous studies demonstrating high diagnostic performance of CTA compared with invasive coronary angiography. However, CTA assessment of coronary stenoses tends toward overestimation, and even among CTA-identified severe stenosis confirmed at the time of invasive coronary angiography, only a minority are found to be ischemia causing. Recent advances in computational fluid dynamics and image-based modeling now permit determination of rest and hyperemic coronary flow and pressure from CTA scans, without the need for additional imaging, modification of acquisition protocols, or administration of medications. These techniques have been used to noninvasively compute fractional flow reserve (FFR), which is the ratio of maximal coronary blood flow through a stenotic artery to the blood flow in the hypothetical case that the artery was normal, using CTA images. In the recently reported prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study and the DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) trial, FFR derived from CTA was demonstrated as superior to measures of CTA stenosis severity for determination of lesion-specific ischemia. Given the significant interest in this novel method for determining the physiological significance of coronary artery disease, we herein present a review on the scientific principles that underlie this technology. © 2013 by the American College of Cardiology Foundation.


Lin J.,Cedars Sinai Heart Institute
Journal of the American Heart Association | Year: 2013

The clinical benefits of the left internal thoracic artery-to-left anterior descending coronary artery graft are well established in coronary artery bypass graft surgery (CABG). However, limited data are available regarding the long-term outcome of the radial artery (RA) as a secondary conduit over the established standard of the saphenous venous graft. We compared the 12-year survival outcome in a set of propensity-matched CABG patients who received either the RA or the saphenous vein as a secondary conduit. A multivariable logistic regression that included 18 baseline characteristics was used to define the propensity of receiving an RA graft. The propensity model resulted in 260 matched pairs who underwent first-time isolated CABG from 1996 to 2001 with similar preoperative characteristics (C statistic=0.86). The cumulative 12-year survival estimated by use of the Kaplan-Meier method was higher for the RA graft patients (hazard ratio 0.76; P=0.03). This survival advantage was especially significant in diabetics (P=0.005), in women (P=0.02), and in the elderly (P=0.04.) The protective effect appeared beginning at year 5 post surgical intervention. The RA as a secondary conduit provided superior long-term survival after CABG, especially in diabetic patients, women, and the elderly. This effect was most pronounced >5 years after surgery.


Zaya M.,Cedars Sinai Heart Institute | Mehta P.K.,Cedars Sinai Heart Institute | Bairey Merz C.N.,Cedars Sinai Heart Institute
Journal of the American College of Cardiology | Year: 2014

Coronary spasm is an important and often overlooked etiology of chest pain. Although coronary spasm, or Prinzmetal's angina, has been thought of as benign, contemporary studies have shown serious associated adverse outcomes, including acute coronary syndrome, arrhythmia, and death. Definitive diagnosis of coronary spasm can at times be difficult, given the transience of symptoms. Numerous agents have been historically described for provocative testing. We provide a review of published data for the role of provocation testing in the diagnosis of coronary spasm.


Cho H.C.,Cedars Sinai Heart Institute | Marban E.,Cedars Sinai Heart Institute
Circulation Research | Year: 2010

Cardiac rhythm disorders reflect failures of impulse generation and/or conduction. With the exception of ablation methods that yield selective endocardial destruction, present therapies are nonspecific and/or palliative. Progress in understanding the underlying biology opens up prospects for new alternatives. This article reviews the present state of the art in gene-and cell-based therapies to correct cardiac rhythm disturbances. We begin with the rationale for such approaches, briefly discuss efforts to address aspects of tachyarrhythmia, and review advances in creating a biological pacemaker to cure bradyarrhythmia. Insights gained bring the field closer to a paradigm shift away from devices and drugs, and toward biologics, in the treatment of rhythm disorders. © 2010 American Heart Association. All rights reserved.


Kobashigawa J.A.,Cedars Sinai Heart Institute
American Journal of Transplantation | Year: 2012

The field of heart transplantation has seen significant progress in the past 40 years. However, the breakthroughs in long-term outcome have seen stagnation in the past decade. Through advances in genomics and transcriptomics, there is hope that an era of personalized transplant therapy lies in the future. To see where heart transplantation truly fits into the long term, searching for and understanding the alternative approaches for heart failure therapy is both important and inevitable. The application of mechanical circulatory support has contributed to the largest advancement in treatment of end stage heart failure. It has already been approved for destination therapy of heart failure, and greater portability and ease of use of the device will be the future trend. Although it is still not prime time for stem cell therapy, clinical experiences have already suggested its potential therapeutic effects. And finally, whole organ engineering is on the horizon as new techniques have opened the way for this to proceed. In the end, progress on alternative therapies largely depends on our deeper understanding of the mechanisms of heart failure and how to prevent it. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.


Shah P.K.,Cedars Sinai Heart Institute
Current Opinion in Cardiology | Year: 2010

PURPOSE OF REVIEW: To provide an update on high-density lipoprotein (HDL) biology and emerging new HDL-based therapies for athero-thrombosis. RECENT FINDINGS: Atherosclerotic cardiovascular disease remains a major public health threat despite a significant decline over the past three decades. Although current medical therapies, specifically low-density lipoprotein lowering with statins, reduce cardiovascular events by about 25-35%, a substantial residual risk remains, leading to a search for additional therapeutic interventions. In this regard, HDL has emerged as one important target because of epidemiologic evidence linking HDL levels inversely to cardiovascular events, known vascular protective actions of HDL and experimental and clinical research supporting athero-protective actions of HDL. However, complexities of HDL composition, particle size, and metabolism have suggested that HDL functionality, and how HDL is increased, may be important determinants of its protective effects. SUMMARY: Thus the possibility that HDL modification could address the residual risk has brought renewed focus on an old HDL-raising drug, niacin, and a number of newer strategies to exploit the vascular benefits of HDL. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Shah P.K.,Cedars Sinai Heart Institute
Journal of the American College of Cardiology | Year: 2010

Unheralded vaso-occlusive cardiovascular events (myocardial infarction, sudden death, and stroke) are common manifestations of atherothrombotic vascular disease, and accurate identification of individuals at risk of such events is highly desirable. Risk factor assessment and management have been the cornerstones of preventive strategies but are constrained by less than desirable accuracy and less than optimal compliance, respectively. In selected populations, noninvasive imaging using carotid ultrasound and/or coronary calcium score can incrementally refine risk assessment and may allow for improved adherence and better matching of preventive interventions to the magnitude of risk. Further refinements in the future may also be possible with novel biomarkers and measures of plaque phenotype. © 2010 American College of Cardiology Foundation.


Marban E.,Cedars Sinai Heart Institute
Mayo Clinic Proceedings | Year: 2014

The clinical reality of cell therapy for heart disease dates back to the 1990s, when autologous skeletal myoblasts were first transplanted into failing hearts during open-chest surgery. Since then, the focus has shifted to bone marrowederived cells and, more recently, cells extracted from the heart itself. Although progress has been nonlinear and often disheartening, the field has nevertheless made remarkable progress. Six major breakthroughs are notable: (1) the establishment of safety with intracoronary delivery; (2) the finding that therapeutic regeneration is possible; (3) the increase in allogeneic cell therapy; (4) the effect of increasing mechanistic insights; (5) glimmers of clinical efficacy; and (6) the progression to phase 2 and 3 studies. This article individually reviews these landmark developments in detail and concludes that the field has reached a new phase of maturity where the prospect of clinical impact is increasingly imminent. © 2014 Mayo Foundation for Medical Education and Research.


Shah P.K.,Cedars Sinai Heart Institute
Current Cardiology Reports | Year: 2014

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted. © 2014, Springer Science+Business Media New York.


Kapoor N.,Cedars Sinai Heart Institute | Liang W.,Cedars Sinai Heart Institute | Marban E.,Cedars Sinai Heart Institute | Cho H.C.,Cedars Sinai Heart Institute
Nature Biotechnology | Year: 2013

The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the ∼5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18, a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.

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