Publications by authors named "Jason C Kovacic"

169 Publications

Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype.

J Clin Invest 2021 Aug;131(15)

Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.
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http://dx.doi.org/10.1172/JCI131178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321575PMC
August 2021

Direct Reprogramming Induces Vascular Regeneration Post Muscle Ischemic Injury.

Mol Ther 2021 Jul 28. Epub 2021 Jul 28.

Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 10029; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 10029; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 10029. Electronic address:

Reprogramming non-cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells is a promising strategy for cardiac regeneration in conditions such as ischemic heart disease. Here, we used a modified mRNA (modRNA) gene delivery platform to deliver a cocktail of four cardiac-reprogramming genes (Gata4 (G), Mef2c (M), Tbx5 (T) and Hand2 (H)) together with three reprogramming-helper genes (Dominant Negative (DN)-TGFβ, DN-Wnt8a and Acid ceramidase (AC)), termed 7G-modRNA, to induce CM-like cells. We showed that 7G-modRNA reprogrammed 57% of CM-like cells in vitro. Through a lineage-tracing model, we determined that delivering the 7G-modRNA cocktail at the time of myocardial infarction reprogrammed ∼25% of CM-like cells in the scar area and significantly improved cardiac function, scar size, long-term survival and capillary density. Mechanistically, we determined that while 7G-modRNA cannot create de-novo beating CMs in vitro or in vivo, it can significantly upregulate pro-angiogenic mesenchymal stromal cells markers and transcription factors. We also demonstrated that our 7G-modRNA cocktail leads to neovascularization in ischemic-limb injury, indicating CM-like cells importance in other organs besides the heart. modRNA is currently being used around the globe for vaccination against COVID-19, and this study proves this is a safe, highly efficient gene delivery approach with therapeutic potential to treat ischemic diseases.
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http://dx.doi.org/10.1016/j.ymthe.2021.07.014DOI Listing
July 2021

Pulmonary Artery F-Fluorodeoxyglucose Uptake by PET/CMR as a Marker of Pulmonary Hypertension in Sarcoidosis.

JACC Cardiovasc Imaging 2021 Jul 8. Epub 2021 Jul 8.

BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Objectives: This study investigated whether pulmonary artery (PA) F-FDG uptake is associated with hypertension, and if it correlates to elevated pulmonary pressures.

Background: F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography or cardiac magnetic resonance (CMR) has been used to assess inflammation mostly in large arteries of the systemic circulation. Much less is known about inflammation of the vasculature of the pulmonary system and its relationship to pulmonary hypertension (PH).

Methods: In a single-center cohort of 175 patients with suspected cardiac sarcoidosis, who underwent hybrid thoracic PET/CMR, F-FDG uptake in the PA was quantified according to maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) and compared with available results from right heart catheterization (RHC) or transthoracic echocardiography (TTE).

Results: Thirty-three subjects demonstrated clear F-FDG uptake in the PA wall. In the subgroup of patients who underwent RHC (n = 10), the mean PA pressure was significantly higher in the group with PA F-FDG uptake compared with the group without uptake (34.4 ± 7.2 mm Hg vs 25.6 ± 9.3 mm Hg; P = 0.003), and 9 (90%) patients with PA F-FDG uptake had PH when a mean PA pressure cutoff of 25 mm Hg was used compared with 18 (45%) in the nonuptake group (P < 0.05). In the subgroup that underwent TTE, signs of PH were present in a significantly higher number of patients with PA F-FDG uptake (14 [51.9%] vs 37 [29.8%]; P < 0.05). Qualitative assessment of F-FDG uptake in the PA wall showed a sensitivity of 33% and specificity of 96% for separating patients with PH based on RHC-derived PA pressures. SUVmax and TBR in the PA wall correlated with PA pressure derived from RHC and/or TTE.

Conclusions: We demonstrate that F-FDG uptake by PET/CMR in the PA is associated with PH and that its intensity correlates with PA pressure.
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http://dx.doi.org/10.1016/j.jcmg.2021.05.023DOI Listing
July 2021

Air pollution and cardiovascular disease: Can the Australian bushfires and global COVID-19 pandemic of 2020 convince us to change our ways?

Bioessays 2021 09 9;43(9):e2100046. Epub 2021 Jun 9.

Victor Chang Cardiac Research Institute, Sydney, Australia.

Air pollution is a major global challenge for a multitude of reasons. As a specific concern, there is now compelling evidence demonstrating a causal relationship between exposure to airborne pollutants and the onset of cardiovascular disease (CVD). As such, reducing air pollution as a means to decrease cardiovascular morbidity and mortality should be a global health priority. This review provides an overview of the cardiovascular effects of air pollution and uses two major events of 2020-the Australian bushfires and COVID-19 pandemic lockdown-to illustrate the relationship between air pollution and CVD. The bushfires highlight the substantial human and economic costs associated with elevations in air pollution. Conversely, the COVID-19-related lockdowns demonstrated that stringent measures are effective at reducing airborne pollutants, which in turn resulted in a potential reduction in cardiovascular events. Perhaps one positive to come out of 2020 will be the recognition that tough measures are effective at reducing air pollution and that these measures have the potential to stop thousands of deaths from CVD.
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http://dx.doi.org/10.1002/bies.202100046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209912PMC
September 2021

Precision Medicine in Catecholaminergic Polymorphic Ventricular Tachycardia: JACC Focus Seminar 5/5.

J Am Coll Cardiol 2021 May;77(20):2592-2612

Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, UNSW Sydney, Kensington, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

In this final of a 5-part Focus Seminar series on precision medicine, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT). This focus on CPVT allows us to take a "deep dive" and explore the full extent of the precision medicine opportunities for a single cardiovascular condition at a level that was not possible in the preceding articles. As a new paradigm presented in this article, it has become clear that CPVT can occur as either a typical or atypical form. Although there is a degree of overlap between the typical and atypical forms, it is notable that they arise due to different underlying genetic changes, likely exhibiting differing mechanisms of action, and presenting with different phenotypic features. The recognition of these differing forms of CPVT and their different etiologies and mechanisms is an important step toward implementing rapidly emerging precision medicine approaches that will tailor novel therapies to specific gene defects.
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http://dx.doi.org/10.1016/j.jacc.2020.12.073DOI Listing
May 2021

Precision Medicine Approaches to Cardiac Arrhythmias: JACC Focus Seminar 4/5.

J Am Coll Cardiol 2021 May;77(20):2573-2591

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Sydney, New South Wales, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies.
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http://dx.doi.org/10.1016/j.jacc.2021.03.325DOI Listing
May 2021

Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies: JACC Focus Seminar 3/5.

J Am Coll Cardiol 2021 May;77(20):2551-2572

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, New South Wales, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies.
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http://dx.doi.org/10.1016/j.jacc.2020.12.072DOI Listing
May 2021

Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5.

J Am Coll Cardiol 2021 May;77(20):2531-2550

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, UNSW Sydney, Kensington, New South Wales, Australia. Electronic address:

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed "Mendelian vascular diseases," which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.
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http://dx.doi.org/10.1016/j.jacc.2021.04.001DOI Listing
May 2021

Precision Medicine in Cardiovascular Disease: Genetics and Impact on Phenotypes: JACC Focus Seminar 1/5.

J Am Coll Cardiol 2021 May;77(20):2517-2530

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, UNSW Sydney, Kensington, New South Wales, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Our understanding of the genetic basis of cardiovascular diseases (CVDs) has evolved rapidly. This has resulted from a combination of dedicated research in well phenotyped CVD patients, the sequencing of the human genome, and the ready accessibility and decreasing cost of next-generation sequencing technologies. This increased knowledge of the genetic basis of CVDs has heralded the era of precision medicine. This encompasses many elements including improved diagnosis, family screening, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Furthermore, novel insights into genetic mechanisms, clinical rollout of polygenic risk scores for common CVDs, and the promise of genome editing approaches to effectively cure disease represent some of the exciting future endeavors that will change established clinical approaches. This Part 1 of a 5-part series focuses on the underpinnings and fundamental aspects of precision medicine.
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http://dx.doi.org/10.1016/j.jacc.2020.12.071DOI Listing
May 2021

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Cardiovasc Res 2021 Mar 19. Epub 2021 Mar 19.

Department of Hypertension, National Institute of Cardiology, Warsaw, Poland.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string of beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research which has led to improved understandings of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.
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http://dx.doi.org/10.1093/cvr/cvab086DOI Listing
March 2021

Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism.

Circulation 2021 05 25;143(18):1809-1823. Epub 2021 Feb 25.

Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (M.v.S., S.P., H.S.).

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue-specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterize central regulators and networks leading to atherosclerosis.

Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models, as well as experimental studies including chromatin immunoprecipitation DNA-sequencing, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse.

Results: The transcription factor MAFF (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element of the LDLR promoter to transcriptionally downregulate LDLR expression.

Conclusions: The transcription factor was identified as a novel central regulator of an atherosclerosis/CAD-relevant liver network. triggered context-specific expression of and other genes known to affect CAD risk. Our results suggest that is a missing link between inflammation, lipid and lipoprotein metabolism, and a possible treatment target.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124091PMC
May 2021

Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching.

Circulation 2021 Feb 27;143(7):713-726. Epub 2021 Jan 27.

Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, The Netherlands (R.J.G.H., M.M., H.M.d.R.).

Background: Although sex differences in coronary artery disease are widely accepted with women developing more stable atherosclerosis than men, the underlying pathobiology of such differences remains largely unknown. In coronary artery disease, recent integrative systems biological studies have inferred gene regulatory networks (GRNs). Within these GRNs, key driver genes have shown great promise but have thus far been unidentified in women.

Methods: We generated sex-specific GRNs of the atherosclerotic arterial wall in 160 women and age-matched men in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task). We integrated the female GRNs with single-cell RNA-sequencing data of the human atherosclerotic plaque and single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic smooth muscle cell (SMC) lineage-tracing mice.

Results: By comparing sex-specific GRNs, we observed clear sex differences in network activity within the atherosclerotic tissues. Genes more active in women were associated with mesenchymal cells and endothelial cells, whereas genes more active in men were associated with the immune system. We determined that key drivers of GRNs active in female coronary artery disease were predominantly found in (SMCs by single-cell sequencing of the human atherosclerotic plaques, and higher expressed in female plaque SMCs, as well. To study the functions of these female SMC key drivers in atherosclerosis, we examined single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic SMC lineage-tracing mice. The female key drivers were found to be expressed by phenotypically modulated SMCs and affected by Klf4, suggesting that sex differences in atherosclerosis involve phenotypic switching of plaque SMCs.

Conclusions: Our systems approach provides novel insights into molecular mechanisms that underlie sex differences in atherosclerosis. To discover sex-specific therapeutic targets for atherosclerosis, an increased emphasis on sex-stratified approaches in the analysis of multi-omics data sets is warranted.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930467PMC
February 2021

An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.

Nat Commun 2021 01 22;12(1):547. Epub 2021 Jan 22.

Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
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http://dx.doi.org/10.1038/s41467-020-20750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822923PMC
January 2021

Prevalence and prognostic impact of hsCRP elevation are age-dependent in women but not in men undergoing percutaneous coronary intervention.

Catheter Cardiovasc Interv 2021 Jun 25;97(7):E936-E944. Epub 2020 Nov 25.

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: High-sensitivity C-reactive protein (hsCRP) predicts outcomes after percutaneous coronary intervention (PCI).

Objective: We studied the prevalence and prognostic impact of hsCRP elevation according to age in men and women undergoing PCI.

Methods: We included patients undergoing PCI at our center from 2010 until 2017, excluding those with myocardial infarction (MI) on presentation, neoplastic disease and hsCRP >10 mg/L at baseline. Elevated hsCRP was defined as >3 mg/L. The outcome of interest was major adverse cardiac events (MACE) consisting of all-cause death, MI and target vessel revascularization. The association between hsCRP elevation and outcomes was assessed using adjusted Cox models.

Results: 10,432 men and 4,345 women were included. Elevation of hsCRP was present in 25.7% of men and 37.0% of women (p < .01). In men, prevalence of hsCRP elevation was stable across age strata (p  = .42). In women, hsCRP elevation was most prevalent in patients <50 years (44.6%) and decreased stepwise with increasing age (p  < .001). After stratifying the population into age quartiles (Q1: <59 years, Q2: 59-66 years, Q3: 67-74 years, Q4: ≥75 years), hsCRP elevation was associated with increased risk of MACE across all age groups in men (HR [95% CI] Q1: 1.49 [1.12-1.98]; Q2: 1.51 [1.21-2.06]; Q3: 1.76 [1.27-2.51]; Q4: 1.43[1.03-1.97]). In women, hsCRP elevation was associated with increased risk of MACE only among older patients (HR [95% CI] Q1: 1.08 [0.64-0.82]; Q2: 1.52 [0.93-2.46]; Q3: 1.65 [1.08-2.50]; Q4: 1.52 [1.02-1.28]).

Conclusion: Among patients undergoing PCI, prevalence and prognostic value of hsCRP elevation were age-dependent exclusively in women.
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http://dx.doi.org/10.1002/ccd.29402DOI Listing
June 2021

Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 10;76(16):1878-1901

Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, New York.

Sarcoidosis is a complex disease with heterogeneous clinical presentations that can affect virtually any organ. Although the lung is typically the most common organ involved, combined pulmonary and cardiac sarcoidosis (CS) account for most of the morbidity and mortality associated with this disease. Pulmonary sarcoidosis can be asymptomatic or result in impairment in quality of life and end-stage, severe, and/or life-threatening disease. The latter outcome is seen almost exclusively in those with fibrotic pulmonary sarcoidosis, which accounts for 10% to 20% of pulmonary sarcoidosis patients. CS is problematic to diagnose and may cause significant morbidity and death from heart failure or ventricular arrhythmias. The diagnosis of CS usually requires surrogate cardiac imaging biomarkers, as endomyocardial biopsy has relatively low yield, even with directed electrophysiological mapping. Treatment of CS is often multifactorial, involving a combination of antigranulomatous therapy and pharmacotherapy for cardiac arrhythmias and/or heart failure in addition to device placement and cardiac transplantation.
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http://dx.doi.org/10.1016/j.jacc.2020.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808240PMC
October 2020

Multiple independent mechanisms link gene polymorphisms in the region of ZEB2 with risk of coronary artery disease.

Atherosclerosis 2020 10 29;311:20-29. Epub 2020 Aug 29.

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St Vincent's Clinical School, University of NSW, Australia. Electronic address:

Background And Aims: Coronary artery disease (CAD) arises from the interaction of genetic and environmental factors. Although genome-wide association studies (GWAS) have identified multiple risk loci and single nucleotide polymorphisms (SNPs) associated with risk of CAD, they are predominantly located in non-coding or intergenic regions and their mechanisms of effect are largely unknown. Accordingly, our objective was to develop a data-driven informatics pipeline to understand complex CAD risk loci, and to apply this to a poorly understood cluster of SNPs in the vicinity of ZEB2.

Methods: We developed a unique informatics pipeline leveraging a multi-tissue CAD genetics-of-gene-expression dataset, GWAS datasets, and other resources. The pipeline first dissected SNP locations and their linkage disequilibrium relationships, and progressed through analyses of tissue-specific expression quantitative trait loci, and then gene-gene, gene-phenotype, SNP-phenotype relationships. The pipeline concluded by exploring CAD-relevant gene regulatory networks (GRNs).

Results: We identified three independent CAD risk SNPs in close proximity to the ZEB2 coding region (rs6740731, rs17678683 and rs2252641/rs1830321). Our pipeline determined that these SNPs likely act in concert via the atherosclerotic arterial wall and adipose tissues, by governing metabolic and lipid functions. In addition, ZEB2 is the top key driver of a liver-specific GRN that is related to lipid levels, metabolic and anthropometric measures, and CAD severity.

Conclusions: Using a novel informatics pipeline, we disclosed the multi-faceted mechanisms of action of the ZEB2-associated CAD risk SNPs. This pipeline can serve as a roadmap to dissect complex SNP-gene-tissue-phenotype relationships and to reveal targets for tissue- and gene-specific therapeutic interventions.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572841PMC
October 2020

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

Cardiovasc Res 2021 03;117(4):1154-1165

Department of Radiology, Assistance-publique-hôpitaux de Paris, Hopital Européen Georges Pompidou, F-75015 Paris, France.

Aims: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.

Methods And Results: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro.

Conclusions: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.
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http://dx.doi.org/10.1093/cvr/cvaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983006PMC
March 2021

Extracellular Matrix in Ischemic Heart Disease, Part 4/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2219-2235

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute and St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes.
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http://dx.doi.org/10.1016/j.jacc.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269147PMC
May 2020

Myocardial Interstitial Fibrosis in Nonischemic Heart Disease, Part 3/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2204-2218

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins. Furthermore, in addition to an excess of collagen, qualitative changes in collagen fibers also contribute to the detrimental impact of MIF. In this part 3 of a 4-part JACC Focus Seminar, we review the evidence on the complex mechanisms leading to MIF, as well as its contribution to systolic and diastolic cardiac dysfunction and impaired clinical outcomes in patients with nonischemic heart disease.
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http://dx.doi.org/10.1016/j.jacc.2020.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213023PMC
May 2020

Extracellular Matrix in Vascular Disease, Part 2/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2189-2203

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Medium-sized and large arteries consist of 3 layers: the tunica intima, tunica media, and tunica adventitia. The tunica media accounts for the bulk of the vessel wall and is the chief determinant of mechanical compliance. It is primarily composed of circumferentially arranged layers of vascular smooth muscle cells that are separated by concentrically arranged elastic lamellae; a form of extracellular matrix (ECM). The tunica media is separated from the tunica intima and tunica adventitia, the innermost and outermost layers, respectively, by the internal and external elastic laminae. This second part of a 4-part JACC Focus Seminar discusses the contributions of the ECM to vascular homeostasis and pathology. Advances in genetics and proteomics approaches have fostered significant progress in our understanding of vascular ECM. This review highlights the important role of the ECM in vascular disease and the prospect of translating these discoveries into clinical disease biomarkers and potential future therapies.
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http://dx.doi.org/10.1016/j.jacc.2020.03.018DOI Listing
May 2020

Basic Biology of Extracellular Matrix in the Cardiovascular System, Part 1/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2169-2188

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.
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http://dx.doi.org/10.1016/j.jacc.2020.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324287PMC
May 2020

Alignment of Transcatheter Aortic-Valve Neo-Commissures (ALIGN TAVR): Impact on Final Valve Orientation and Coronary Artery Overlap.

JACC Cardiovasc Interv 2020 05 16;13(9):1030-1042. Epub 2020 Mar 16.

Division of Cardiac Surgery, NewYork-Presbyterian Hospital, Columbia University Medical Center, New York, New York.

Objectives: The aim of this study was to evaluate the impact of initial deployment orientation of SAPIEN 3, Evolut, and ACURATE-neo transcatheter heart valves on their final orientation and neocommissural overlap with coronary arteries.

Background: Coronary artery access and redo transcatheter aortic valve replacement (TAVR) following initial TAVR may be influenced by transcatheter heart valve orientation. In this study the impact of transcatheter heart valve deployment orientation on commissural alignment was evaluated.

Methods: Pre-TAVR computed tomography and procedural fluoroscopy were analyzed in 828 patients who underwent TAVR (483 SAPIEN 3, 245 Evolut, and 100 ACURATE-neo valves) from March 2016 to September 2019 at 5 centers. Coplanar fluoroscopic views were coregistered to pre-TAVR computed tomography to determine commissural alignment. Severe overlap between neocommissural posts and coronary arteries was defined as 0° to 20° apart. The SAPIEN 3 had 1 commissural post crimped at 3, 6, 9, and 12 o'clock. The Evolut "Hat" marker and ACURATE-neo commissural post at deployment were classified as center back (CB), inner curve (IC), outer curve (OC), or center front (CF) and matched with final orientation.

Results: Initial SAPIEN 3 crimped orientation had no impact on commissural alignment. Evolut "Hat" at OC or CF at initial deployment had less severe overlap than IC or CB (p < 0.001) against the left main (15.7% vs. 66.0%) and right coronary (7.1% vs. 51.1%) arteries. Tracking Evolut "Hat" at OC of the descending aorta (n = 107) improved OC at deployment from 70.2% to 91.6% (p = 0.002) and reduced coronary artery overlap by 36% to 60% (p < 0.05). ACURATE-neo commissural post at CB or IC during deployment had less coronary artery overlap compared to CF or OC (p < 0.001), with intentional alignment successful in 5 of 7 cases.

Conclusions: This is the first systematic evaluation of commissural alignment in TAVR. More than 30% to 50% of cases had overlap with 1 or both coronary arteries. Initial SAPIEN 3 orientation had no impact on alignment, but specific initial orientations of Evolut and ACURATE improved alignment. Optimizing valve alignment to avoid coronary artery overlap will be important in coronary artery access and redo TAVR.
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http://dx.doi.org/10.1016/j.jcin.2020.02.005DOI Listing
May 2020

Impact of insulin treated and non-insulin-treated diabetes compared to patients without diabetes on 1-year outcomes following contemporary PCI.

Catheter Cardiovasc Interv 2020 08 12;96(2):298-308. Epub 2020 Mar 12.

Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objective: We compared 1-year outcomes in insulin-treated diabetes mellitus (ITDM) and non-ITDM patients compared to nondiabetic (DM) patients following contemporary percutaneous coronary intervention (PCI).

Background: ITDM is associated with extensive atherosclerotic disease and worse cardiovascular prognosis compared to non-ITDM patients.

Methods: We evaluated PCI patients at a large tertiary center from 2010 to 2016, grouped according to diabetes and treatment status at baseline. One-year major adverse cardiac events (MACE) were defined as a composite of death, myocardial infarction (MI), or target vessel revascularization. Outcomes were adjusted using multivariable Cox regression methods.

Results: During the study period, 16,889 patients underwent PCI including 13.7% ITDM, 34.0% non-ITDM, and 52.3% non-DM patients. Patients with DM were younger, including more females and non-white patients, with higher body mass index and greater prevalence of prior revascularization and chronic kidney disease. Compared to others, ITDM patients more often presented with acute coronary syndrome, in-stent restenosis, or severe lesion calcification. There were no differences in discharge rates of dual antiplatelet therapy and statins, whereas beta-blockers were more commonly prescribed in DM patients. At 1-year, both ITDM and non-ITDM patients had greater risk of MACE compared with non-DM patients, and ITDM conferred greater adjusted risk than non-ITDM (ITDM = HR: 2.11, 95% CI [1.79,2.50]; non-ITDM = HR: 1.27, 95%CI [1.09,1.47]).

Conclusions: The negative prognostic effect of DM following contemporary PCI is heightened in the presence of insulin treatment, compared to non-DM patients. Focus on secondary prevention, prescription of and adherence to optimal medical therapy is necessary for post-PCI risk reduction.
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http://dx.doi.org/10.1002/ccd.28841DOI Listing
August 2020

Combined and independent impact of coronary artery calcification and inflammation on risk for adverse cardiovascular events after percutaneous coronary intervention: Results from a large single-center registry.

Catheter Cardiovasc Interv 2020 09 22;96(3):E278-E286. Epub 2020 Feb 22.

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Our study investigated the impact of coronary artery calcification (CAC) and systemic inflammation on risks for major adverse cardiovascular events (MACE) following percutaneous coronary intervention (PCI).

Background: CAC and systemic inflammation are known to be associated with an increased risk of cardiovascular events.

Methods: A total of 17,711 consecutive patients who underwent PCI in our hospital between January 1, 2009 and December 31, 2015 were categorized according to the degree of CAC (moderate/severe vs. none/mild) and high-sensitivity C-reactive protein (hsCRP) level (≥2 vs. <2 mg/L). MACE was defined as death, myocardial infarction (MI), or target vessel revascularization (TVR) occurring over 1 year.

Results: Within the four groups, patients with both moderate/severe CAC and elevated hsCRP (n = 1,814 [10.2%]) were older with more comorbid risk factors compared to those with moderate/severe CAC alone (n = 1,687 [9.5%]), elevated hsCRP alone (n = 7,597 [42.9%]) or neither abnormality (n = 6,613 [37.3%]). The analogous 1-year MACE rates were 21.2, 14.9, 11.5, and 7.8%, respectively (p-trend < .001). Results were unchanged after multivariable adjustment, suggesting synergistic adverse effects in patients with both CAC and elevated hsCRP.

Conclusions: The presence of both moderate/severe CAC and systemic inflammation confers a synergistic effect on risk for MACE following PCI, indicating the need for novel or more intense therapeutic interventions to mitigate risk in such patients.
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http://dx.doi.org/10.1002/ccd.28784DOI Listing
September 2020

4-Dimensional Transesophageal Echocardiographic Guidance During TAVR With BASILICA.

JACC Cardiovasc Imaging 2020 07 15;13(7):1601-1614. Epub 2020 Jan 15.

Division of Cardiology, Mount Sinai Health System, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2019.11.022DOI Listing
July 2020

Tissue-Resident PDGFRα Progenitor Cells Contribute to Fibrosis versus Healing in a Context- and Spatiotemporally Dependent Manner.

Cell Rep 2020 01;30(2):555-570.e7

Cardiovascular Institute, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA. Electronic address:

PDGFRα mesenchymal progenitor cells are associated with pathological fibro-adipogenic processes. Conversely, a beneficial role for these cells during homeostasis or in response to revascularization and regeneration stimuli is suggested, but remains to be defined. We studied the molecular profile and function of PDGFRα cells in order to understand the mechanisms underlying their role in fibrosis versus regeneration. We show that PDGFRα cells are essential for tissue revascularization and restructuring through injury-stimulated remodeling of stromal and vascular components, context-dependent clonal expansion, and ultimate removal of pro-fibrotic PDGFRα-derived cells. Tissue ischemia modulates the PDGFRα phenotype toward cells capable of remodeling the extracellular matrix and inducing cell-cell and cell-matrix adhesion, likely favoring tissue repair. Conversely, pathological healing occurs if PDGFRα-derived cells persist as terminally differentiated mesenchymal cells. These studies support a context-dependent "yin-yang" biology of tissue-resident mesenchymal progenitor cells, which possess an innate ability to limit injury expansion while also promoting fibrosis in an unfavorable environment.
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http://dx.doi.org/10.1016/j.celrep.2019.12.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030884PMC
January 2020

Assessing the qualitative and quantitative impacts of simple two-class vs multiple tissue-class MR-based attenuation correction for cardiac PET/MR.

J Nucl Cardiol 2020 Jan 2. Epub 2020 Jan 2.

Translational and Molecular Imaging Institute, Leon and Norma Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Pl, 1470 Madison Ave, TMII - 1st floor, New York, NY, 10029, USA.

Background: Hybrid PET/MR imaging has significant potential in cardiology due to its combination of molecular PET imaging and cardiac MR. Multi-tissue-class MR-based attenuation correction (MRAC) is necessary for accurate PET quantification. Moreover, for thoracic PET imaging, respiration is known to lead to misalignments of MRAC and PET data that result in PET artifacts. These factors can be addressed by using multi-echo MR for tissue segmentation and motion-robust or motion-gated acquisitions. However, the combination of these strategies is not routinely available and can be prone to errors. In this study, we examine the qualitative and quantitative impacts of multi-class MRAC compared to a more widely available simple two-class MRAC for cardiac PET/MR.

Methods And Results: In a cohort of patients with cardiac sarcoidosis, we acquired MRAC data using multi-echo radial gradient-echo MR imaging. Water-fat separation was used to produce attenuation maps with up to 4 tissue classes including water-based soft tissue, fat, lung, and background air. Simultaneously acquired 18F-fluorodeoxyglucose PET data were subsequently reconstructed using each attenuation map separately. PET uptake values were measured in the myocardium and compared between different PET images. The inclusion of lung and subcutaneous fat in the MRAC maps significantly affected the quantification of 18F-fluorodeoxyglucose activity in the myocardium but only moderately altered the appearance of the PET image without introduction of image artifacts.

Conclusion: Optimal MRAC for cardiac PET/MR applications should include segmentation of all tissues in combination with compensation for the respiratory-related motion of the heart. Simple two-class MRAC is adequate for qualitative clinical assessment.
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http://dx.doi.org/10.1007/s12350-019-02002-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329599PMC
January 2020

Current challenges in TAVI: neo-commissural alignment to mimic more physiologic valve implantation.

Vessel Plus 2020 10;4. Epub 2020 Dec 10.

Department of Cardiovascular Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Commissural alignment during transcatheter aortic valve implantation (TAVI) has important clinical implications as TAVI expands to younger patients in whom lifetime treatment of aortic valve disease and coronary artery disease is of particular importance. Numerous studies have shown that lack of commissural alignment may adversely affect coronary reaccess and the feasibility of redo-TAVI in this patient population. To assess the risk of commissural misalignment more accurately, we have pioneered and validated the use of a preprocedural imaging protocol that determines valve orientation using multi-detector computed tomography-fluoroscopy co-registration. Furthermore, we have shown that a modified delivery system insertion technique during initial valve deployment results in improved commissural alignment and reduced coronary artery overlap following TAVI with a self-expanding device. However, numerous unanswered questions remain about the impact of commissural misalignment on balloon-expandable valve-in-valve TAVI, especially in patients with unfavorable aortic root anatomy. It is imperative that clinicians consider these anatomic, device-related, and procedure factors, among others, when evaluating patients for transcatheter therapies.
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http://dx.doi.org/10.20517/2574-1209.2020.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171260PMC
December 2020
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