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Chong T, Lan NSR, Courtney W, He A, Strange G, Playford D, Dwivedi G, Hillis GS, Ihdayhid AR. Medical Therapy to Prevent or Slow Progression of Aortic Stenosis: Current Evidence and Future Directions. Cardiol Rev 2024; 32:473-482. [PMID: 36961371 DOI: 10.1097/crd.0000000000000528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
Degenerative aortic stenosis is a growing clinical problem owing to the high incidence in an aging population and its significant morbidity and mortality. Currently, aortic valve replacement remains the only treatment. Despite promising observational data, pharmacological management to slow or halt progression of aortic stenosis has remained elusive. Nevertheless, with a greater understanding of the mechanisms which underpin aortic stenosis, research has begun to explore novel treatment strategies. This review will explore the historical agents used to manage aortic stenosis and the emerging agents that are currently under investigation.
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Affiliation(s)
- Travis Chong
- From the Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
| | - Nick S R Lan
- From the Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
- Internal Medicine, Medical School, The University of Western Australia, Perth, Australia
| | - William Courtney
- Internal Medicine, Medical School, The University of Western Australia, Perth, Australia
- Department of Cardiology, Royal Perth Hospital, Perth, Australia
| | - Albert He
- From the Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
| | - Geoff Strange
- School of Medicine, University of Notre Dame, Fremantle, Australia
| | - David Playford
- School of Medicine, University of Notre Dame, Fremantle, Australia
| | - Girish Dwivedi
- From the Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
- Internal Medicine, Medical School, The University of Western Australia, Perth, Australia
| | - Graham S Hillis
- Internal Medicine, Medical School, The University of Western Australia, Perth, Australia
- Department of Cardiology, Royal Perth Hospital, Perth, Australia
| | - Abdul Rahman Ihdayhid
- From the Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
- Curtin Medical School, Curtin University, Perth, Australia
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2
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Venema CS, van Bergeijk KH, Hadjicharalambous D, Andreou T, Tromp J, Staal L, Krikken JA, van der Werf HW, van den Heuvel AF, Douglas YL, Lipsic E, Voors AA, Wykrzykowska JJ. Prediction of the Individual Aortic Stenosis Progression Rate and its Association With Clinical Outcomes. JACC. ADVANCES 2024; 3:100879. [PMID: 38939659 PMCID: PMC11198185 DOI: 10.1016/j.jacadv.2024.100879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/22/2023] [Accepted: 01/12/2024] [Indexed: 06/29/2024]
Abstract
Background The progression rate of aortic stenosis differs between patients, complicating clinical follow-up and management. Objectives This study aimed to identify predictors associated with the progression rate of aortic stenosis. Methods In this retrospective longitudinal single-center cohort study, all patients with moderate aortic stenosis who presented between December 2011 and December 2022 and had echocardiograms available were included. The individual aortic stenosis progression rate was calculated based on aortic valve area (AVA) from at least 2 echocardiograms performed at least 6 months apart. Baseline factors associated with the progression rate of AVA were determined using linear mixed-effects models, and the association of progression rate with clinical outcomes was evaluated using Cox regression. Results The study included 540 patients (median age 69 years and 38% female) with 2,937 echocardiograms (median 5 per patient). Patients had a linear progression with a median AVA decrease of 0.09 cm2/y and a median peak jet velocity increase of 0.17 m/s/y. Rapid progression was independently associated with all-cause mortality (HR: 1.77, 95% CI: 1.26-2.48) and aortic valve replacement (HR: 3.44, 95% CI: 2.55-4.64). Older age, greater left ventricular mass index, atrial fibrillation, and chronic kidney disease were associated with a faster decline of AVA. Conclusions AVA decreases linearly in individual patients, and faster progression is independently associated with higher mortality. Routine clinical and echocardiographic variables accurately predict the individual progression rate and may aid clinicians in determining the optimal follow-up interval for patients with aortic stenosis.
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Affiliation(s)
- Constantijn S. Venema
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Kees. H. van Bergeijk
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Demetra Hadjicharalambous
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Theodora Andreou
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Jasper Tromp
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
- Saw Swee Hock School of Public Health, National University of Singapore, and the National University Health System, Singapore, Singapore
| | - Laura Staal
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Jan A. Krikken
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Hindrik W. van der Werf
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Ad F.M. van den Heuvel
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Yvonne L. Douglas
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Erik Lipsic
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Adriaan A. Voors
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Joanna J. Wykrzykowska
- Department of Cardiology and Cardiothoracic Surgery, Heart Centre, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
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Seo JH, Kim KH, Chun KJ, Lee BK, Cho BR, Ryu DR. Impact of low-density lipoprotein cholesterol on progression of aortic valve sclerosis and stenosis. Front Cardiovasc Med 2023; 10:1171703. [PMID: 37529711 PMCID: PMC10390070 DOI: 10.3389/fcvm.2023.1171703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/08/2023] [Indexed: 08/03/2023] Open
Abstract
Background Little research has been assessed atherosclerotic risk factors at various stages of calcific aortic valve disease. This study sought to determine risk factors of patients with aortic valve sclerosis (AVS) and mild to moderate aortic stenosis (AS). Methods The study included 1,007 patients diagnosed with AVS or mild to moderate AS according to echocardiographic criteria. Patients were identified as a rapid progression group if the annualized difference in peak aortic jet velocity (Vmax) between two echocardiographic examinations was >0.08 m/s/yr in AVS and >0.3 m/s/yr in AS, respectively. We used multivariable logistic regression analyses to assess the factors associated with rapid disease progression or progression to severe AS. Results Among 526 AVS patients, higher LDL-C level (odds ratio [OR] 1.22/per 25 mg/dl higher LDL-C, 95% confidence interval [CI] 1.05-1.43) was significantly associated with rapid disease progression. Compared to patients with LDL-C level <70 mg/dl, the adjusted OR for rapid progression were 1.32, 2.15, and 2.98 for those with LDL-C level of 70-95 mg/dl, 95-120 mg/dl, and ≥120 mg/dl, respectively. Among 481 mild to moderate AS patients, the baseline Vmax (OR 1.79/per 0.5 m/s higher Vmax, 95% CI 1.18-2.70) was associated with rapid progression. Compared to patients with Vmax 2.0-2.5 m/s, the adjusted OR for rapid progression were 2.47, 2.78, and 3.49 for those with Vmax of 2.5-3.0 m/s, 3.0-3.5 m/s, and 3.5-4.0 m/s, respectively. LDL-C and baseline Vmax values were independently associated with progression to severe AS. Conclusion Atherosclerotic risk factors such as LDL-C were significantly associated with the rapid progression in AVS and baseline Vmax was important in the stage of mild to moderate AS.
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Statins in High Cardiovascular Risk Patients: Do Comorbidities and Characteristics Matter? Int J Mol Sci 2022; 23:ijms23169326. [PMID: 36012589 PMCID: PMC9409457 DOI: 10.3390/ijms23169326] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins are the drug of choice for patients at increased risk of ASCVD and remain one of the most commonly used and effective drugs for reducing LDL cholesterol and the risk of mortality and coronary artery disease in high-risk groups. Unfortunately, doctors tend to under-prescribe or under-dose these drugs, mostly out of fear of side effects. The latest guidelines emphasize that treatment intensity should increase with increasing cardiovascular risk and that the decision to initiate intervention remains a matter of individual consideration and shared decision-making. The purpose of this review was to analyze the indications for initiation or continuation of statin therapy in different categories of patient with high cardiovascular risk, considering their complexity and comorbidities in order to personalize treatment.
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Greenberg HZE, Zhao G, Shah AM, Zhang M. Role of oxidative stress in calcific aortic valve disease and its therapeutic implications. Cardiovasc Res 2022; 118:1433-1451. [PMID: 33881501 PMCID: PMC9074995 DOI: 10.1093/cvr/cvab142] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.
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Affiliation(s)
- Harry Z E Greenberg
- Department of Cardiology, Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Guoan Zhao
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University, Heart Center of Xinxiang Medical University, Henan, China
| | - Ajay M Shah
- Department of Cardiology, Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Min Zhang
- Department of Cardiology, Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
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Nordquist EM, Dutta P, Kodigepalli KM, Mattern C, McDermott MR, Trask AJ, LaHaye S, Lindner V, Lincoln J. Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury. Arterioscler Thromb Vasc Biol 2021; 41:2923-2942. [PMID: 34645278 PMCID: PMC8612994 DOI: 10.1161/atvbaha.121.316450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/23/2021] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response to injury and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16-18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 (Tgfβ1) and the glycoprotein, collagen triple helix repeat containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. CONCLUSIONS Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.
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Affiliation(s)
- Emily M. Nordquist
- Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA
- Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA
- The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Punashi Dutta
- Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA
- The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Karthik M. Kodigepalli
- Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA
- The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Carol Mattern
- Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA
- The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Michael R. McDermott
- Center for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Aaron J. Trask
- Center for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Stephanie LaHaye
- The Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Volkhard Lindner
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA
| | - Joy Lincoln
- Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA
- The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
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Dutta P, Kodigepalli KM, LaHaye S, Thompson JW, Rains S, Nagel C, Thatcher K, Hinton RB, Lincoln J. KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway. Circ Res 2021; 128:1300-1316. [PMID: 33601919 PMCID: PMC8085092 DOI: 10.1161/circresaha.120.318503] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Punashi Dutta
- Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Pediatric Cardiology, The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Karthik M. Kodigepalli
- Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Pediatric Cardiology, The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Stephanie LaHaye
- The Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH, USA
| | - J. Will Thompson
- Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Sarah Rains
- Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
- Duke Proteomics and Metabolomics Shared Resource, Durham, NC, USA
| | - Casey Nagel
- Ocean Ridge Biosciences, Deerfield Beach, Florida, USA
| | - Kaitlyn Thatcher
- Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Pediatric Cardiology, The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Robert B. Hinton
- Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Joy Lincoln
- Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Pediatric Cardiology, The Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI, USA
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8
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Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers. Int J Mol Sci 2021; 22:ijms22073569. [PMID: 33808189 PMCID: PMC8037707 DOI: 10.3390/ijms22073569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. METHODS Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. RESULTS The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. CONCLUSION Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.
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9
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Lee W, Choi W, Kang SH, Hwang IC, Choi HM, Yoon YE, Cho GY. Long-term Prognosis of Mild to Moderate Aortic Stenosis and Coronary Artery Disease. J Korean Med Sci 2021; 36:e47. [PMID: 33559407 PMCID: PMC7870422 DOI: 10.3346/jkms.2021.36.e47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 12/02/2020] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND There is an incomplete understanding of the natural course of mild to moderate aortic stenosis (AS). We aimed to evaluate the natural course of patients with mild to moderate AS and its association with coronary artery disease (CAD). METHODS We retrospectively analyzed 787 patients diagnosed with mild to moderate AS using echocardiography between 2004 and 2010. Cardiac death and aortic valve replacement (AVR) for AS were assessed. RESULTS A median follow-up period was 92 months. Compared to the general population, patients with mild to moderate AS had a higher risk of cardiac death (hazard ratio [HR], 17.16; 95% confidence interval [CI], 13.65-21.59; P < 0.001). Established CAD was detected in 22.4% and associated with a significantly higher risk of cardiac mortality (adjusted HR, 1.62; 95% CI, 1.04-2.53; P = 0.033). The risk of cardiac death was lower when patients were taking statin (adjusted HR, 0.64; 95% CI, 0.41-0.98; P = 0.041), which was clear only after 7 years. Both patients with CAD and on statin tended to undergo more AVR, but the difference was not statistically significant (the presence of established CAD; adjusted HR, 1.63; 95% CI, 0.51-3.51; P = 0.214 and the use of statin; adjusted HR, 1.86; 95% CI, 0.76-4.58; P = 0.177). CONCLUSION Mild to moderate AS does not have a benign course. The presence of CAD and statin use may affect the long-term prognosis of patients with mild to moderate AS.
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Affiliation(s)
- Wonjae Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Wonsuk Choi
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Si Hyuck Kang
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - In Chang Hwang
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hong Mi Choi
- Division of Cardiology, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Yeonyee E Yoon
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Goo Yeong Cho
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea.
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10
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Chan C, Foster ST, Chan KG, Cacace MJ, Ladd SL, Sandum CT, Wright PT, Volmert B, Yang W, Aguirre A, Li W, Wright NT. Repositioned Drugs for COVID-19-the Impact on Multiple Organs. SN COMPREHENSIVE CLINICAL MEDICINE 2021; 3:1484-1501. [PMID: 33898925 PMCID: PMC8057921 DOI: 10.1007/s42399-021-00874-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/22/2021] [Indexed: 02/02/2023]
Abstract
This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.
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Affiliation(s)
- Christina Chan
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA ,Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI USA ,Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Sean T. Foster
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Kayla G. Chan
- Integrative Neuroscience Program, Binghamton University, Binghamton, NY USA
| | - Matthew J. Cacace
- Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA USA
| | - Shay L. Ladd
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Caleb T. Sandum
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Paul T. Wright
- Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA USA
| | - Brett Volmert
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Weiyang Yang
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Aitor Aguirre
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Wen Li
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Neil T. Wright
- Department of Mechanical Engineering, Michigan State University, East Lansing, MI USA
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11
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Capoulade R, Cariou B. Editorial commentary: Lp(a) and calcific aortic valve stenosis: Direct LPA targeting or PCSK9-Lowering therapy? Trends Cardiovasc Med 2020; 31:312-314. [PMID: 32623063 DOI: 10.1016/j.tcm.2020.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 06/25/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Romain Capoulade
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France.
| | - Bertrand Cariou
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France
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12
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Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111-188. [PMID: 31504418 DOI: 10.1093/eurheartj/ehz455] [Citation(s) in RCA: 5179] [Impact Index Per Article: 1035.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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13
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Kontogeorgos S, Thunström E, Basic C, Hansson PO, Zhong Y, Ergatoudes C, Morales D, Mandalenakis Z, Rosengren A, Caidahl K, Fu M. Prevalence and risk factors of aortic stenosis and aortic sclerosis: a 21-year follow-up of middle-aged men. SCAND CARDIOVASC J 2019; 54:115-123. [PMID: 31674218 DOI: 10.1080/14017431.2019.1685126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Introduction. There is limited knowledge about factors associated with the development of aortic stenosis. This study aimed to examine the prevalence of aortic sclerosis or stenosis in 71-years-old men and determine which risk factors at 50 years of age predict the development of aortic sclerosis or aortic stenosis. Methods. A random sample of Swedish men from the general population, born in 1943 (n = 798) were followed for 21 years. Data on clinical characteristics and laboratory values were collected in 1993. An echocardiography was performed in 2014. We used logistic regression to examine the association between baseline data and the outcome. Results. Echocardiography was performed in 535 men, and aortic sclerosis or aortic stenosis was diagnosed in 27 (5.0%). 14 persons developed aortic stenosis (2.6%). Among men with aortic sclerosis or aortic stenosis, 29.6% were obese. In multivariable stepwise regression model, body mass index (odds ratio per unit increase 1.23 (95% CI 1.10-1.38; p = .0003)) and hypercholesterolemia, combined with high sensitive C-reactive protein (odds ratio versus all other 2.66 (1.18-6.00; p = .019)) were significantly associated with increased risk of developing aortic sclerosis or aortic stenosis. Body mass index was the only factor significantly associated with a higher risk of developing aortic stenosis. Conclusion. The prevalence of either aortic sclerosis or aortic stenosis was 5% and of aortic stenosis 2.6%. Obesity and hypercholesterolemia combined with elevated high sensitive C-reactive protein at the age of 50 predicted the development of degenerative aortic sclerosis or stenosis, whilst only obesity was correlated with the occurrence of aortic stenosis.
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Affiliation(s)
- Silvana Kontogeorgos
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Erik Thunström
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Carmen Basic
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Per-Olof Hansson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - You Zhong
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Cardiology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Constantinos Ergatoudes
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - David Morales
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Zacharias Mandalenakis
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Annika Rosengren
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Kenneth Caidahl
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Michael Fu
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
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14
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Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, Windecker S, Aboyans V, Baigent C, Collet JP, Dean V, Delgado V, Fitzsimons D, Gale CP, Grobbee D, Halvorsen S, Hindricks G, Iung B, Jüni P, Katus HA, Landmesser U, Leclercq C, Lettino M, Lewis BS, Merkely B, Mueller C, Petersen S, Petronio AS, Richter DJ, Roffi M, Shlyakhto E, Simpson IA, Sousa-Uva M, Touyz RM, Nibouche D, Zelveian PH, Siostrzonek P, Najafov R, van de Borne P, Pojskic B, Postadzhiyan A, Kypris L, Špinar J, Larsen ML, Eldin HS, Viigimaa M, Strandberg TE, Ferrières J, Agladze R, Laufs U, Rallidis L, Bajnok L, Gudjónsson T, Maher V, Henkin Y, Gulizia MM, Mussagaliyeva A, Bajraktari G, Kerimkulova A, Latkovskis G, Hamoui O, Slapikas R, Visser L, Dingli P, Ivanov V, Boskovic A, Nazzi M, Visseren F, Mitevska I, Retterstøl K, Jankowski P, Fontes-Carvalho R, Gaita D, Ezhov M, Foscoli M, Giga V, Pella D, Fras Z, Perez de Isla L, Hagström E, Lehmann R, Abid L, Ozdogan O, Mitchenko O, Patel RS. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis 2019; 290:140-205. [PMID: 31591002 DOI: 10.1016/j.atherosclerosis.2019.08.014] [Citation(s) in RCA: 657] [Impact Index Per Article: 109.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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15
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Andrault PM, Panwar P, Mackenzie NCW, Brömme D. Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification. Sci Rep 2019; 9:9682. [PMID: 31273243 PMCID: PMC6609650 DOI: 10.1038/s41598-019-45918-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 06/07/2019] [Indexed: 12/13/2022] Open
Abstract
Elastin plays an important role in maintaining blood vessel integrity. Proteolytic degradation of elastin in the vascular system promotes the development of atherosclerosis, including blood vessel calcification. Cysteine cathepsins have been implicated in this process, however, their role in disease progression and associated complications remains unclear. Here, we showed that the degradation of vascular elastin by cathepsins (Cat) K, S, and V directly stimulates the mineralization of elastin and that mineralized insoluble elastin fibers were ~25–30% more resistant to CatK, S, and V degradation when compared to native elastin. Energy dispersive X-ray spectroscopy investigations showed that insoluble elastin predigested by CatK, S, or V displayed an elemental percentage in calcium and phosphate up to 8-fold higher when compared to non-digested elastin. Cathepsin-generated elastin peptides increased the calcification of MOVAS-1 cells acting through the ERK1/2 pathway by 34–36%. We made similar observations when cathepsin-generated elastin peptides were added to ex vivo mouse aorta rings. Altogether, our data suggest that CatK-, S-, and V-mediated elastolysis directly accelerates the mineralization of the vascular matrix by the generation of nucleation points in the elastin matrix and indirectly by elastin-derived peptides stimulating the calcification by vascular smooth muscle cells. Both processes inversely protect against further extracellular matrix degradation.
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Affiliation(s)
- Pierre-Marie Andrault
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T1Z3, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Preety Panwar
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T1Z3, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Neil C W Mackenzie
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T1Z3, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Dieter Brömme
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T1Z3, Canada. .,Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. .,Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T1Z3, Canada.
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16
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Bicuspid aortic valve, atherosclerosis and changes of lipid metabolism: Are there pathological molecular links? J Mol Cell Cardiol 2019; 129:231-235. [DOI: 10.1016/j.yjmcc.2019.03.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/03/2019] [Accepted: 03/07/2019] [Indexed: 12/19/2022]
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17
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Abstract
PURPOSE OF REVIEW Recent literature is examined to identify established and emerging risk factors for valvular calcification, specifically calcific aortic valve disease and mitral annular calcification. RECENT FINDINGS Strong evidence implicates older age, male sex, cigarette smoking, elevated blood pressure, dyslipidaemia, adiposity, and mineral metabolism as risk factors for calcific aortic valve disease. Emerging evidence suggests family history and lipoprotein(a) are additional risk factors. Recently, large-scale genome-wide analyses have identified robust associations for LPA, PALMD, and TEX41 with aortic stenosis. Factors predisposing to mitral annular calcification are less well characterized. Older age, cigarette smoking, increased BMI, kidney dysfunction, and elevated triglycerides are associated with greater risk of mitral annular calcification, but conflicting evidence exists for sex and C-reactive protein. SUMMARY Established and emerging risk factors for calcific aortic valve disease, including some that overlap with atherosclerosis, may represent targets for pharmacological intervention. Mitral annular calcification is comparatively less well understood though some atherosclerosis risk factors do appear to increase risk.
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Affiliation(s)
- Hao Yu Chen
- Division of Experimental Medicine, McGill University, Montreal, Canada
- Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada
| | - James C. Engert
- Division of Experimental Medicine, McGill University, Montreal, Canada
- Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
| | - George Thanassoulis
- Division of Experimental Medicine, McGill University, Montreal, Canada
- Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada
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18
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Seo JH, Chun KJ, Lee BK, Cho BR, Ryu DR. Statins Have No Role in Preventing the Progression of Aortic Valve Sclerosis. J Cardiovasc Imaging 2018; 26:229-237. [PMID: 30607391 PMCID: PMC6310758 DOI: 10.4250/jcvi.2018.26.e27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/30/2018] [Accepted: 11/20/2018] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Statins are thought to have little effect on the progression of aortic stenosis, but the data on their role in patients with aortic valve sclerosis (AVS) are limited and inconsistent. METHODS We retrospectively analyzed 541 consecutive patients (214 men, age: 70 ± 11 years) with AVS. Each patient underwent two or more electrocardiography examinations at least 6 months apart at Kangwon National University Hospital from August 2010 to August 2015. AVS is defined as irregular thickening of the leaflets, focal increases in echogenicity and minimal elevation of the peak aortic valve velocity (> 1.5 and < 2 m/s). The progression rate of AVS was expressed as the increase in peak velocity per year (m/s/yr). RESULTS The mean follow-up duration was 24.9 ± 13.3 months in the statin-treated group and 24.1 ± 12.4 months in the non-statin-treated group (p = 0.460). There were no differences between the statin-treated and non-statin-treated groups in mean age, gender or smoking status. Relative to the non-statin-treated group, a higher number of patients in the statin-treated group had hypertension, diabetes, ischemic heart disease, and stroke. The progression rate of AVS did not differ between the statin-treated and non-statin-treated groups (0.012 ± 0.340 m/s/yr vs. 0.014 ± 0.245 m/s/yr, p = 0.956). Multivariate analysis showed initial peak aortic jet velocity was significantly associated with AVS progression (β = 0.153, p = 0.009). CONCLUSIONS Our study demonstrated that statins had no effect on the progression of AVS. However, well-designed studies are needed to define the prognosis and management of AVS.
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Affiliation(s)
- Jeong-Hun Seo
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea
| | - Kwang-Jin Chun
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Bong-Ki Lee
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Byung-Ryul Cho
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Dong Ryeol Ryu
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
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19
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Menon V, Lincoln J. The Genetic Regulation of Aortic Valve Development and Calcific Disease. Front Cardiovasc Med 2018; 5:162. [PMID: 30460247 PMCID: PMC6232166 DOI: 10.3389/fcvm.2018.00162] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/19/2018] [Indexed: 12/19/2022] Open
Abstract
Heart valves are dynamic, highly organized structures required for unidirectional blood flow through the heart. Over an average lifetime, the valve leaflets or cusps open and close over a billion times, however in over 5 million Americans, leaflet function fails due to biomechanical insufficiency in response to wear-and-tear or pathological stimulus. Calcific aortic valve disease (CAVD) is the most common valve pathology and leads to stiffening of the cusp and narrowing of the aortic orifice leading to stenosis and insufficiency. At the cellular level, CAVD is characterized by valve endothelial cell dysfunction and osteoblast-like differentiation of valve interstitial cells. These processes are associated with dysregulation of several molecular pathways important for valve development including Notch, Sox9, Tgfβ, Bmp, Wnt, as well as additional epigenetic regulators. In this review, we discuss the multifactorial mechanisms that contribute to CAVD pathogenesis and the potential of targeting these for the development of novel, alternative therapeutics beyond surgical intervention.
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Affiliation(s)
- Vinal Menon
- Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States
| | - Joy Lincoln
- Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, Ohio State University, Columbus, OH, United States
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20
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Novel pharmacological targets for calcific aortic valve disease: Prevention and treatments. Pharmacol Res 2018; 136:74-82. [DOI: 10.1016/j.phrs.2018.08.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/24/2022]
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21
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The role of OPG/RANKL in the pathogenesis of diabetic cardiovascular disease. Cardiovasc Endocrinol Metab 2018; 7:28-33. [PMID: 31646276 DOI: 10.1097/xce.0000000000000144] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/21/2017] [Indexed: 11/25/2022]
Abstract
Cardiovascular (CV) disease is the leading cause of mortality in patients with type 2 diabetes mellitus. A major factor in the pathogenesis of CV disease is vascular calcification (VC), which is accelerated in type 2 diabetes mellitus. Calcification of the vessel wall contributes to vascular stiffness and left ventricular hypertrophy whereas intimal calcification may predispose to plaque rupture and CV death. The pathogenesis of VC is complex but appears to be regulated by the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) signaling pathway, which is involved in bone remodeling. Within the bone, OPG prevents RANKL from binding to receptor activator of nuclear factor-κB and inhibiting bone resorption. Outside of the bone, the clinical significance of OPG blocking RANKL is not well understood, but OPG knockout mice that lack OPG develop early and severe VC. This minireview outlines some of the research on OPG/RANKL in the pathogenesis of VC and discusses potential therapies, which may reduce VC and CV burden in humans.
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22
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Abstract
PURPOSE OF REVIEW This review aims to highlight the past and more current literature related to the multifaceted pathogenic programs that contribute to calcific aortic valve disease (CAVD) with a focus on the contribution of developmental programs. RECENT FINDINGS Calcification of the aortic valve is an active process characterized by calcific nodule formation on the aortic surface leading to a less supple and more stiffened cusp, thereby limiting movement and causing clinical stenosis. The mechanisms underlying these pathogenic changes are largely unknown, but emerging studies have suggested that signaling pathways common to valvulogenesis and bone development play significant roles and include Transforming Growth Factor-β (TGF-β), bone morphogenetic protein (BMP), Wnt, Notch, and Sox9. This comprehensive review of the literature highlights the complex nature of CAVD but concurrently identifies key regulators that can be targeted in the development of mechanistic-based therapies beyond surgical intervention to improve patient outcome.
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23
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Tastet L, Capoulade R, Shen M, Clavel MA, Côté N, Mathieu P, Arsenault M, Bédard É, Tremblay A, Samson M, Bossé Y, Dumesnil JG, Arsenault BJ, Beaudoin J, Bernier M, Després JP, Pibarot P. ApoB/ApoA-I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study. J Am Heart Assoc 2018; 7:JAHA.117.007980. [PMID: 29440006 PMCID: PMC5850203 DOI: 10.1161/jaha.117.007980] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Previous studies reported that middle-aged patients with atherogenic lipoprotein-lipid profile exhibit faster progression of aortic valve stenosis (AS). The ratio of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) reflects the balance between atherogenic and anti-atherogenic lipoproteins. The aim of this study was to examine the association between apoB/apoA-I ratio and AS hemodynamic progression and to determine whether this association varies according to age. METHODS AND RESULTS A total of 159 patients (66±13 years, 73% men) with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. Hemodynamic progression of AS was determined by the change in peak aortic jet velocity (Vpeak) measured by Doppler-echocardiography between baseline and 2-year follow-up. Patients in the top tertile of apoB/apoA-I ratio (≥0.62) had a faster progression rate of AS compared with those in the bottom/mid tertiles (Vpeak progression: 0.30 [0.09-0.49] versus 0.16 [0.01-0.36] m/s, P=0.02). There was a significant interaction (P=0.007) between apoB/apoA-I ratio and age. Among younger patients (ie, aged <70 years; median value of the cohort), those in the top tertile of apoB/apoA-I ratio had a 3.4-fold faster AS progression compared with those in the bottom/mid tertiles (Vpeak progression: 0.34 [0.13-0.69] versus 0.10 [-0.03-0.31] m/s, P=0.002), whereas there was no significant difference between tertiles in the subgroup of older patients (P=0.83). After comprehensive adjustment, higher apoB/apoA-I ratio was significantly associated with faster AS progression in the subset of younger patients (all, standardized β≥0.36; P≤0.01). CONCLUSIONS Higher apoB/apoA-I ratio is significantly associated with faster hemodynamic progression of AS in the younger patients. These findings suggest that atherogenic lipid factors may play a crucial role in the pathogenesis of AS in younger patients, but may be are less important in older patients. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT01679431.
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Affiliation(s)
- Lionel Tastet
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Romain Capoulade
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Mylène Shen
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Marie-Annick Clavel
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Nancy Côté
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Patrick Mathieu
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Marie Arsenault
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Élisabeth Bédard
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Alexe Tremblay
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Marilie Samson
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Yohan Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Jean G Dumesnil
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Benoit J Arsenault
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Jonathan Beaudoin
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Mathieu Bernier
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
| | - Philippe Pibarot
- Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada
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24
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Sengeløv M, Cheng S, Biering-Sørensen T, Matsushita K, Konety S, Solomon SD, Folsom AR, Shah AM. Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients. J Am Heart Assoc 2018; 7:JAHA.117.007234. [PMID: 29431107 PMCID: PMC5850241 DOI: 10.1161/jaha.117.007234] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Background The relationship between ideal cardiovascular health reflected in the cardiovascular health score (CVHS) and valvular heart disease is not known. The purpose of this study was to determine the association of CVHS attainment through midlife to late life with aortic stenosis prevalence and severity in late life. Methods and Results The following 6 ideal cardiovascular health metrics were assessed in ARIC (Atherosclerosis Risk in Communities) Study participants at 5 examination visits between 1987 and 2013 (visits 1–4 in 1987–1998 and visit 5 in 2011–2013): smoking, body mass index, total cholesterol, blood pressure, physical activity, and blood glucose. Percentage attained CVHS was calculated in 6034 participants as the sum of CVHS at each visit/the maximum possible score. Aortic stenosis was assessed by echocardiography at visit 5 on the basis of the peak aortic valve velocity. Aortic stenosis was categorized sclerosis, mild stenosis, and moderate‐to‐severe stenosis. Mean age was 76±5 years, 42% were men, and 22% were black. Mean percentage attained CVHS was 63±14%, and the prevalence of aortic stenosis stages were 15.9% for sclerosis, 4.3% for mild stenosis, and 0.7% for moderate‐to‐severe stenosis. Worse percentage attained CVHS was associated with higher prevalence of aortic sclerosis (P<0.001 for trend), mild stenosis (P<0.001), and moderate‐to‐severe stenosis (P=0.002), adjusting for age, sex, and race. Conclusions Greater attainment of ideal cardiovascular health in midlife to late life is associated with a lower prevalence of aortic sclerosis and stenosis in late life in a large cohort of older adults.
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Affiliation(s)
- Morten Sengeløv
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA
| | - Susan Cheng
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA
| | | | - Kunihiro Matsushita
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Suma Konety
- Division of Cardiology, University of Minnesota, Minneapolis, MN
| | - Scott D Solomon
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA
| | - Aaron R Folsom
- Division of Epidemiology and Community Health, and School of Public Health, University of Minnesota, Minneapolis, MN
| | - Amil M Shah
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA
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Effect of pioglitazone on inflammation and calcification in atherosclerotic rabbits : An 18F-FDG-PET/CT in vivo imaging study. Herz 2017; 43:733-740. [PMID: 28956073 DOI: 10.1007/s00059-017-4620-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 08/20/2017] [Accepted: 08/28/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND We developed an atherosclerotic rabbit model and tested pioglitazone as a drug intervention for early vascular calcification. Positron emission tomography/computed tomography (PET/CT) was used to evaluate inflammation and therapeutic effects. METHODS We randomly divided 20 male New Zealand white rabbits into a pioglitazone-treated group (n = 10) and a control group (n = 10). Atherosclerosis was induced via a high-cholesterol diet and endothelial denudation. The animals were maintained on a hyperlipidemic diet for 16 weeks after surgery, and the treatment group received pioglitazone daily. Serum samples were obtained at 8 and 18 weeks postoperatively to assess high-sensitivity C‑reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) concentrations. Sixteen rabbits underwent a mid-stage PET/CT scan at week 8, and 11 rabbits underwent an end-stage PET/CT scan at week 18. PET/CT parameters, including the mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax), were measured and documented. RESULTS There were significantly lower hs-CRP and MMP-9 levels in the pioglitazone group at week 18 (p < 0.01). At the end of the 8th week, no significant between-group differences in SUVmean and SUVmax were observed. From week 8 to week 18, the SUVmean and SUVmax decreased in the pioglitazone group but the SUVmean increased in the control group, with significant between-group differences at the end of the 18th week (p < 0.01). Histopathological examination of aortas in the control and pioglitazone groups revealed significantly smaller plaque area, macrophage density, and tissue calcification area in the latter group. CONCLUSION Pioglitazone affects early vascular microcalcification, and pioglitazone-induced changes can be assessed using 18F-FDG-PET/CT.
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Akin I, Nienaber CA. Is there evidence for statins in the treatment of aortic valve stenosis? World J Cardiol 2017; 9:667-672. [PMID: 28932355 PMCID: PMC5583539 DOI: 10.4330/wjc.v9.i8.667] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/21/2017] [Accepted: 06/06/2017] [Indexed: 02/06/2023] Open
Abstract
Research revealed that the pathogenesis of aortic stenosis (AS) not merely comprises of a mechanical wear and tear process yet that active biological processes, similar to those of coronary artery disease are involved, a promising role for statins in disease-modifying therapy was suggested. However, recently, many prospective studies could not observe decreased progression nor regression of the disease. Here, we review the current knowledge on the pathomechanisms of AS and its similarities and differences with atherosclerosis. Moreover, we discuss whether there is still a place for statins in the treatment of particular AS patient subgroups.
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Affiliation(s)
- Ibrahim Akin
- Medical Faculty Mannheim, University Heidelberg, 68167 Mannheim, Germany
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Lee SH, Kim DH, Youn YN, Lee S, Joo HC, Chang BC, Yoo KJ. Effect of Rosuvastatin on Bovine Pericardial Aortic Tissue Valve Calcification in a Rat Subdermal Implantation Model. Korean Circ J 2017; 47:401-408. [PMID: 28567091 PMCID: PMC5449535 DOI: 10.4070/kcj.2016.0214] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 10/27/2016] [Accepted: 02/16/2017] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND AND OBJECTIVES There are pathophysiologic similarities between calcification and atherosclerosis because both are the product of an active inflammatory process. The aim of this study was to examine the effects of statin treatment on calcification in bovine pericardial tissue valves. MATERIALS AND METHODS Forty Sprague-Dawley rats were randomly divided into 4 groups according to hypercholesterolemia induction and statin intake (Group 1, n=10: normal diet without statin treatment, Group 2, n=10: normal diet with statin treatment, Group 3, n=10: high fat diet without statin treatment, Group 4, n=10: high fat diet with statin treatment). Serum lipid levels were measured just before the experiment and after 4 and 12 weeks. Bovine pericardial tissue valve cusps were surgically implanted in rat dorsal subcutis at 4 weeks. After the surgery, statin was administered daily to Groups 2 and 4. Serum interleukin-6 (IL-6) level was measured at 5 weeks. Cusps were explanted at 12 weeks and calcium levels were determined by atomic absorption spectroscopy. RESULTS Mean IL-6 was significantly higher in Group 3 at 5 weeks (7.14, 2.03, 31.70, and 6.90 pg/dL for each group, respectively). Mean calcium level in Group 3 was significantly higher among groups but Group 4 was significantly lower compared to Group 3 and was similar to Group 1, 2 (1.86, 1.92, 2.55, and 1.80 mg/g for each group, respectively, p<0.01). CONCLUSION Hypercholesterolemia may be a significant risk factor for bovine pericardial valve calcification. Statin treatment significantly attenuated calcification of bovine pericardial valve tissue in a rat subdermal implantation model and might prolong the durability of bioprostheses.
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Affiliation(s)
- Seung Hyun Lee
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Dae-Hyun Kim
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Nam Youn
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sak Lee
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Chel Joo
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Chul Chang
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung-Jong Yoo
- Division of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
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Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration. Curr Opin Cardiol 2017; 32:123-129. [DOI: 10.1097/hco.0000000000000372] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abstract
Randomized, double-blind, placebo-controlled secondary prevention and primary prevention studies and observational studies have documented that statins reduce cardiovascular events in high-risk patients with hypercholesterolemia. The 2013 American College of Cardiology/American Heart Association guidelines on treatment of hypercholesterolemia support the use of statins in 4 major groups that will be discussed. The Expert Panel of these guidelines could find no data supporting the routine use of nonstatin drugs combined with statins to further reduce cardiovascular events. Since these guidelines were published, a double-blind randomized trial of 18,144 patients with an acute coronary syndrome demonstrated at a 7-year follow-up that the incidence of cardiovascular events was 34.7% in patients randomized to simvastatin plus placebo versus 32.7% in patients randomized to simvastatin plus ezetimibe (hazard ratio = 0.936; P = 0.016). Proprotein convertase subtilisin/kexin type 9 inhibitors further lower serum low-density lipoprotein cholesterol by 50%-70% in patients treated with statins and 4 phase 3 trials including more than 70,000 patients are investigating whether these monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 will lower cardiovascular events.
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Affiliation(s)
- Wilbert S Aronow
- Division of Cardiology, Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY
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Abstract
Objective: To review the evidence evaluating the efficacy of statins in reducing the progression of calcified aortic stenosis (AS). Data Sources: MEDLINE, EMBASE, and PubMed were searched (all up to November 2006) for studies evaluating the use of statins to reduce the progression of calcified AS. Search terms included statin, HMG CoA reductase inhibitor, calcified AS, valve stenosis, and calcified stenosis. Additional primary trials were located by searching references noted in review articles. Study Selection and Data Extraction: Clinical trials published in the English language were selected for review. Primary efficacy outcomes evaluated were changes in aortic valve measurements, hemodynamic measures of AS, and change in measures of AS severity. Data Synthesis: TWO prospective clinical trials and 5 retrospective studies were included in this review. All of the retrospective studies demonstrated that statin use was associated with a statistically significant delay in the progression of AS. One prospective observation trial showed benefit of statin use; however, a large, randomized, double-blind, prospective trial showed no benefit of statin use in decreasing the progression of AS. Conclusions: An association between statin use and a delay in AS progression has been observed in retrospective studies; however, prospective trials showed conflicting results. Currently, statins cannot be recommended for medical treatment of AS until larger trials are conducted.
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Affiliation(s)
- Doson Chua
- St. Paul's Hospital, Vancouver, BC, Canada.
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Enger TB, Pleym H, Stenseth R, Greiff G, Wahba A, Videm V. Reduced Long-Term Relative Survival in Females and Younger Adults Undergoing Cardiac Surgery: A Prospective Cohort Study. PLoS One 2016; 11:e0163754. [PMID: 27681368 PMCID: PMC5040400 DOI: 10.1371/journal.pone.0163754] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/13/2016] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES To assess long-term survival and mortality in adult cardiac surgery patients. METHODS 8,564 consecutive patients undergoing cardiac surgery in Trondheim, Norway from 2000 until censoring 31.12.2014 were prospectively followed. Observed long-term mortality following surgery was compared to the expected mortality in the Norwegian population, matched on gender, age and calendar year. This enabled assessment of relative survival (observed/expected survival rates) and relative mortality (observed/expected deaths). Long-term mortality was compared across gender, age and surgical procedure. Predictors of reduced survival were assessed with multivariate analyses of observed and relative mortality. RESULTS During follow-up (median 6.4 years), 2,044 patients (23.9%) died. The observed 30-day, 1-, 3- and 5-year mortality rates were 2.2%, 4.4%, 8.2% and 13.8%, respectively, and remained constant throughout the study period. Comparing observed mortality to that expected in a matched sample from the general population, patients undergoing cardiac surgery showed excellent survival throughout the first seven years of follow-up (relative survival ≥ 1). Subsequently, survival decreased, which was more pronounced in females and patients undergoing other procedures than isolated coronary artery bypass grafting (CABG). Relative mortality was higher in younger age groups, females and patients undergoing aortic valve replacement (AVR). The female survival advantage in the general population was obliterated (relative mortality ratio (RMR) 1.35 (1.19-1.54), p<0.001). Increasing observed long-term mortality seen with ageing was due to population risk, and younger age was independently associated with increased relative mortality (RMR per 5 years 0.81 (0.79-0.84), p<0.001)). CONCLUSIONS Cardiac surgery patients showed comparable survival to that expected in the general Norwegian population, underlining the benefits of cardiac surgery in appropriately selected patients. The beneficial effect lasted shorter in younger patients, females and patients undergoing AVR or other procedures than isolated CABG. Thus, the study identified three groups that need increased attention for further improvement of outcomes.
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Affiliation(s)
- Tone Bull Enger
- Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiothoracic Anaesthesia and Intensive Care, St. Olavs University Hospital, Trondheim, Norway
| | - Hilde Pleym
- Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Anaesthesia and Intensive Care, St. Olavs University Hospital, Trondheim, Norway
| | - Roar Stenseth
- Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiothoracic Anaesthesia and Intensive Care, St. Olavs University Hospital, Trondheim, Norway
| | - Guri Greiff
- Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiothoracic Anaesthesia and Intensive Care, St. Olavs University Hospital, Trondheim, Norway
| | - Alexander Wahba
- Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Cardiothoracic Surgery, St. Olavs University Hospital, Trondheim, Norway
| | - Vibeke Videm
- Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway
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Thiago L, Tsuji SR, Nyong J, Puga MES, Gois AFT, Macedo CR, Valente O, Atallah ÁN, Cochrane Heart Group. Statins for aortic valve stenosis. Cochrane Database Syst Rev 2016; 9:CD009571. [PMID: 27594276 PMCID: PMC6457620 DOI: 10.1002/14651858.cd009571.pub2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Aortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis. OBJECTIVES To evaluate the effectiveness and safety of statins in aortic valve stenosis. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions. SELECTION CRITERIA Randomised controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care. DATA COLLECTION AND ANALYSIS Primary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalisation for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table. MAIN RESULTS We included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalisation for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life. AUTHORS' CONCLUSIONS Result findings showed uncertainty surrounding the effect of statins for aortic valve stenosis.The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis.
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Affiliation(s)
- Luciana Thiago
- Marilia Medical SchoolDepartment of Education in Health SciencesMariliaBrazil
| | - Selma Rumiko Tsuji
- Marilia Medical SchoolDepartment of Psychiatry and Evidence Based Health ActionsAv. Monte Carlo, 800MariliaMariliaBrazil17519‐030
| | - Jonathan Nyong
- University College LondonInstitute of Health Informatics222 Euston RoadLondonUKNW1 2DA
| | - Maria ES Puga
- Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em SaúdeBrazilian Cochrane CentreRua Borges Lagoa, 564 cj 63São PauloSão PauloBrazil04038‐000
| | - Aecio FT Gois
- Escola Paulista de Medicina, Universidade Federal de São PauloBrazilian Cochrane CentreRua Pedro de Toledo, 598São PauloSão PauloBrazil04039‐001
| | - Cristiane R Macedo
- Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em SaúdeBrazilian Cochrane CentreRua Borges Lagoa, 564 cj 63São PauloSão PauloBrazil04038‐000
| | - Orsine Valente
- Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em SaúdeBrazilian Cochrane CentreRua Borges Lagoa, 564 cj 63São PauloSão PauloBrazil04038‐000
| | - Álvaro N Atallah
- Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em SaúdeBrazilian Cochrane CentreRua Borges Lagoa, 564 cj 63São PauloSão PauloBrazil04038‐000
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Harper E, Forde H, Davenport C, Rochfort KD, Smith D, Cummins PM. Vascular calcification in type-2 diabetes and cardiovascular disease: Integrative roles for OPG, RANKL and TRAIL. Vascul Pharmacol 2016; 82:30-40. [DOI: 10.1016/j.vph.2016.02.003] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 02/01/2016] [Accepted: 02/21/2016] [Indexed: 12/14/2022]
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Pate GE, Tahir MN, Murphy RT, Foley JB. Anti-inflammatory Effects of Statins in Patients with Aortic Stenosis. J Cardiovasc Pharmacol Ther 2016; 8:201-6. [PMID: 14506545 DOI: 10.1177/107424840300800305] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: Aortic stenosis is an inflammatory process, as evidenced by increased tissue expression and serum levels of various endothelial cellular adhesion molecules. Aortic stenosis and atherosclerosis have many risk factors in common, including hypercholesterolemia. In atherosclerosis, statins lower cholesterol and display some anti-inflammatory activity. We hypothesized that statins might also have anti-inflammatory effects in patients with aortic stenosis. Methods: This observational cross-sectional study measured levels of cellular adhesion molecules in 129 patients (88 male, mean age 68) with aortic stenosis (mean echo gradient 49 mm Hg, range 22 to 112) and compared levels in patients already on statin therapy for primary or secondary prevention of coronary artery disease, to those not on treatment. Concomitant conditions included hypertension (47%), diabetes (10%), and ischemic heart disease (54%). A comparison group consisted of 45 patients with stable ischemic heart disease. Results: Patients on statins (35) were more likely to have hypertension (62% vs 42%, P = .05), but no significant differences existed in sex, age, concomitant ischemic heart disease, or diabetes. Statin-treated patients had a 20% lower vascular cellular adhesion molecule level than those without (484 ± 143 ng/L vs 604 ± 245 ng/L, P = .006). The reduction in cellular adhesion molecule levels was consistent in patients with aortic stenosis alone, aortic stenosis and ischemic heart disease, or ischemic heart disease alone. There were no differences in the levels of the other adhesion molecules between the three groups, or related to statin therapy. Conclusion: Statin therapy is associated with reduced serum levels of vascular cellular adhesion molecules in patients with aortic stenosis. Vascular cellular adhesion molecule levels are similar in patients who have aortic stenosis, ischemic heart disease, or both. A prospective study is required to confirm this finding and to determine whether this suppression of endothelial inflammation translates into a slowing of the progression of aortic stenosis.
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Affiliation(s)
- Gordon E Pate
- Department of Cardiology, CresT Directorate, St. James's Hospital, Dublin 8, Ireland
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Madhu MN, Aguiar C, Hassan A, Brunt KR. Translating calcified aortic valve disease to the bench - Use of 3D matrices in the development of future treatment strategies. J Mol Cell Cardiol 2016; 98:58-61. [PMID: 27338001 DOI: 10.1016/j.yjmcc.2016.06.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 06/18/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Malav N Madhu
- Department of Pharmacology, Dalhousie Medicine New Brunswick, Canada; Faculty of Medicine, Dalhousie University, Canada
| | - Christie Aguiar
- Department of Cardiac Surgery, Saint John Regional Hospital, Canada
| | - Ansar Hassan
- Department of Cardiac Surgery, Saint John Regional Hospital, Canada; Faculty of Medicine, Dalhousie University, Canada
| | - Keith R Brunt
- Department of Pharmacology, Dalhousie Medicine New Brunswick, Canada; Faculty of Medicine, Dalhousie University, Canada.
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Pasca I, Dang P, Tyagi G, Pai RG. Survival in Patients with Degenerative Mitral Stenosis: Results from a Large Retrospective Cohort Study. J Am Soc Echocardiogr 2016; 29:461-469. [PMID: 26936152 DOI: 10.1016/j.echo.2015.12.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND Severe mitral annular calcification causing degenerative mitral stenosis (DMS) is increasingly encountered in patients undergoing mitral and aortic valve interventions. However, its clinical profile and natural history and the factors affecting survival remain poorly characterized. The goal of this study was to characterize the factors affecting survival in patients with DMS. METHODS An institutional echocardiographic database was searched for patients with DMS, defined as severe mitral annular calcification without commissural fusion and a mean transmitral diastolic gradient of ≥2 mm Hg. This resulted in a cohort of 1,004 patients. Survival was analyzed as a function of clinical, pharmacologic, and echocardiographic variables. RESULTS The patient characteristics were as follows: mean age, 73 ± 14 years; 73% women; coronary artery disease in 49%; and diabetes mellitus in 50%. The 1- and 5-year survival rates were 78% and 47%, respectively, and were slightly worse with higher DMS grades (P = .02). Risk factors for higher mortality included greater age (P < .0001), atrial fibrillation (P = .0009), renal insufficiency (P = .004), mitral regurgitation (P < .0001), tricuspid regurgitation (P < .0001), elevated right atrial pressure (P < .0001), concomitant aortic stenosis (P = .02), and low serum albumin level (P < .0001). Adjusted for propensity scores, use of renin-angiotensin system blockers (P = .02) or statins (P = .04) was associated with better survival, and use of digoxin was associated with higher mortality (P = .007). CONCLUSIONS Prognosis in patients with DMS is poor, being worse in the aged and those with renal insufficiency, atrial fibrillation, and other concomitant valvular lesions. Renin-angiotensin system blockers and statins may confer a survival benefit, and digoxin use may be associated with higher mortality in these patients.
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Affiliation(s)
- Ioana Pasca
- Division of Anesthesiology, Loma Linda University Medical Center, Loma Linda, California
| | - Patricia Dang
- Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California
| | - Gaurav Tyagi
- Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California
| | - Ramdas G Pai
- Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California.
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Zhao Y, Nicoll R, He YH, Henein MY. The effect of statins on valve function and calcification in aortic stenosis: A meta-analysis. Atherosclerosis 2016; 246:318-24. [DOI: 10.1016/j.atherosclerosis.2016.01.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/13/2016] [Accepted: 01/15/2016] [Indexed: 12/31/2022]
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Zhao Y, Nicoll R, He YH, Henein MY. The effect of statins therapy in aortic stenosis: Meta-analysis comparison data of RCTs and observationals. Data Brief 2016; 7:357-61. [PMID: 26977437 PMCID: PMC4781966 DOI: 10.1016/j.dib.2016.02.045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 02/11/2016] [Accepted: 02/18/2016] [Indexed: 11/30/2022] Open
Abstract
Aortic stenosis has been shown to share the same risk factors as atherosclerosis which suggested a potential benefit from statins therapy. Fourteen studies which provided the effect of statins treatment on aortic stenosis (AS) were meta-analyzed, including 5 randomized controlled trials (RCTs) and 9 observational studies. In the RCTs, statins did not have any influence on peak aortic valve velocity, peak valve gradient, mean valve gradient, aortic valve area and aortic calcification compared to controls. In the observational studies, the peak valve velocity, peak gradient and aortic valve area showed less progression in the statins group compared to controls. This article describes data related article title “The effect of statins on valve function and calcification in aortic stenosis: a meta-analysis” (Zhao et al., 2016) [1].
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Affiliation(s)
- Ying Zhao
- Ultrasound Department, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Rachel Nicoll
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Yi Hua He
- Ultrasound Department, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Michael Y Henein
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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Calcific aortic valve disease: is it another face of atherosclerosis? Indian Heart J 2015; 67:503-6. [PMID: 26432749 DOI: 10.1016/j.ihj.2015.07.033] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/23/2015] [Accepted: 07/16/2015] [Indexed: 11/22/2022] Open
Abstract
Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the elderly. As life expectancy increases, prevalence of CAVD is expected to rise. CAVD is characterized by progressive dystrophic calcification of aortic cusps. In the initial stages, the pathogenesis is similar to atherosclerosis, characterized by basement membrane disruption, inflammation, cell infiltration, lipid deposition, and calcification. Presence of osteopontin in calcified aortic valves suggests pathological calcification and bone formation in these calcified valves. Historical, experimental, genetic, and clinical evidences suggest that CAVD and atherosclerosis share the same pathological sequences with common risk factors. Understanding the two faces of atherosclerosis, the vascular and valvular, will help us to prevent progression of aortic sclerosis to aortic stenosis, by controlling modifiable risk factors and by initiating statin therapy in them. However, the knowledge about these preventive measures and drugs is scanty. In this review article, an attempt is made to unfurl the relation between atherosclerosis and CAVD.
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Differing relationship between hypercholesterolemia and a bicuspid aortic valve according to the presence of aortic valve stenosis or aortic valve regurgitation. Gen Thorac Cardiovasc Surg 2015; 63:502-6. [PMID: 26033769 DOI: 10.1007/s11748-015-0561-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Accepted: 05/16/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To assess the difference in hyperlipidemia between patients with bicuspid aortic valve (BAV) and those with a normal aortic valve (NAV), and to compare aortic valve stenosis (AS), with aortic valve regurgitation (AR). METHODS Among 32 patients with BAV and 142 patients with NAV who underwent aortic valve replacement, 81 patients had AR and 91 patients had AS. The preoperative clinical characteristics were compared between the BAV and NAV patients. Patients with replacement of the ascending aorta were included, and those who underwent combined valvular surgery, coronary artery bypass grafting, or statin treatment were excluded. RESULTS The proportions of females patients (p = 0.42), patients with diabetes (p = 0.26) and patients on dialysis (p = 0.69) were similar in the two groups. Mean age was significantly lower, the mean diameter of the ascending aorta was significantly larger, and the rate of surgical intervention for the ascending aorta was significantly higher in the BAV group than in the NAV group (all p < 0.0001). The mean levels of low-density lipoprotein cholesterol (LDL) (p < 0.0001) and total cholesterol (TC) (p = 0.0003) were significantly higher in the BAV group than in the NAV group, in the analysis of only patients with AS, whereas these levels did not differ significantly between the groups, when only patients with AR were considered. CONCLUSION BAV with AS is associated with hypercholesterolemia. However, BAV with AR was not associated with hypercholesterolemia.
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Parisi V, Leosco D, Ferro G, Bevilacqua A, Pagano G, de Lucia C, Perrone Filardi P, Caruso A, Rengo G, Ferrara N. The lipid theory in the pathogenesis of calcific aortic stenosis. Nutr Metab Cardiovasc Dis 2015; 25:519-525. [PMID: 25816732 DOI: 10.1016/j.numecd.2015.02.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/27/2015] [Accepted: 02/02/2015] [Indexed: 01/04/2023]
Abstract
AIMS Biologically active phenomena, triggered by atherogenesis and inflammation, lead to aortic valve (AV) calcification. Lipids play an important role in activating the cell signaling leading to AV bone deposition. This review, based on evidence from animal and human studies, mainly focused on the involvement of lipids and atherogenic phenomena in the pathogenesis of calcific aortic stenosis (AS). DATA SYNTHESIS The role of elevated low density lipoproteins for the risk of both vascular atherosclerosis and AS has been elucidated. Lipid disorders act synergistically with other risk factors to increase prevalence of calcific AS. Atherosclerosis is also involved in the pathogenesis of bone demineralization, a typical hallmark of aging, which is associated with ectopic calcification at vascular and valvular levels. Animal studies have recently contributed to demonstrate that lipids play an important role in AS pathogenesis through the activation of molecular cell signalings, such as Wnt/Lrp5 and RANK/RANKL/Osteprotegerin, which induce the transition of valvular myofibroblasts toward an osteogenic phenotype with consequent valvular bone deposition. Although all these evidence strongly support the lipid theory in AS pathogenesis, lipids lowering therapies failed to demonstrate in controlled trials a significant efficacy to slow AS progression. Encouraging results from animal studies indicate that physical activity may counteract the biological processes inducing AV degeneration. CONCLUSIONS This review indicates a robust interplay between lipids, inflammation, and calcific AS. This new pathophysiological scenario of such an emerging valvular disease paves the way to the next challenge of cardiovascular research: "prevent and care aortic valve stenosis".
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Affiliation(s)
- V Parisi
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy
| | - D Leosco
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy.
| | - G Ferro
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy
| | - A Bevilacqua
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy
| | - G Pagano
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy
| | - C de Lucia
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy
| | - P Perrone Filardi
- Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Italy
| | - A Caruso
- Casa di Cura S. Michele, Maddaloni, Italy
| | - G Rengo
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy; Fondazione S. Maugeri, IRCCS, Istituto di Telese Terme, BN, Italy
| | - N Ferrara
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Italy; Fondazione S. Maugeri, IRCCS, Istituto di Telese Terme, BN, Italy
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Bull S, Loudon M, Francis JM, Joseph J, Gerry S, Karamitsos TD, Prendergast BD, Banning AP, Neubauer S, Myerson SG. A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging 2015; 16:834-41. [PMID: 25796267 PMCID: PMC4505792 DOI: 10.1093/ehjci/jev043] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 02/15/2015] [Indexed: 01/12/2023] Open
Abstract
Aims Angiotensin-converting enzyme (ACE) inhibitors improve left ventricular (LV) remodelling and outcome in heart failure and hypertensive heart disease. They may be similarly beneficial in patients with aortic stenosis (AS), but historical safety concerns have limited their use, and no prospective clinical trials exist. Methods and results We conducted a prospective, randomized, double-blind, placebo-controlled trial in 100 patients with moderate or severe asymptomatic AS to examine the physiological effects of ramipril, particularly LV mass (LVM) regression. Subjects were randomized to ramipril 10 mg daily (n = 50) or placebo (n = 50) for 1 year, and underwent cardiac magnetic resonance, echocardiography, and exercise testing at 0, 6, and 12 months, with follow-up data available in 77 patients. There was a modest but progressive reduction in LVM (the primary end point) in the ramipril group vs. the placebo group (mean change −3.9 vs. +4.5 g, respectively, P = 0.0057). There were also trends towards improvements in myocardial physiology: the ramipril group showed preserved tissue Doppler systolic velocity compared with placebo (+0.0 vs. −0.5 cm/s, P = 0.04), and a slower rate of progression of the AS (valve area 0.0 cm2 in the ramipril group vs. −0.2 cm2 in the placebo arm, P = 0.067). There were no significant differences in major adverse cardiac events. Conclusion ACE inhibition leads to a modest, but progressive reduction in LVM in asymptomatic patients with moderate–severe AS compared with placebo, with trends towards improvements in myocardial physiology and slower progression of valvular stenosis. A larger clinical outcome trial to confirm these findings and explore their clinical relevance is required.
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Affiliation(s)
- Sacha Bull
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Margaret Loudon
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Jane M Francis
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Jubin Joseph
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Stephen Gerry
- Centre for Statistics in Medicine, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK
| | - Theodoros D Karamitsos
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Bernard D Prendergast
- Department of Cardiology, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Adrian P Banning
- Department of Cardiology, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Stefan Neubauer
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Saul G Myerson
- University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK Department of Cardiology, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Aronow WS. Lipid-lowering therapy in older persons. Arch Med Sci 2015; 11:43-56. [PMID: 25861289 PMCID: PMC4379366 DOI: 10.5114/aoms.2015.48148] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 06/01/2013] [Accepted: 06/01/2013] [Indexed: 12/21/2022] Open
Abstract
Numerous randomized, double-blind, placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program III guidelines state that in very high-risk persons, a serum low-density lipoprotein (LDL) cholesterol level of < 70 mg/dl (1.8 mmol/l) is a reasonable clinical strategy for moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary artery disease of 10% to 20%), and the serum LDL cholesterol should be reduced to < 100 mg/dl (2.6 mmol/l). When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced by at least 30% to 40%. The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease. Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality.
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Affiliation(s)
- Wilbert S Aronow
- Department of Medicine, Divisions of Cardiology, Pulmonary Medicine/Critical Care, and Geriatrics, New York Medical College, Valhalla, NY, USA
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Le Ven F, Tizón-Marcos H, Fuchs C, Mathieu P, Pibarot P, Larose E. Valve tissue characterization by magnetic resonance imaging in calcific aortic valve disease. Can J Cardiol 2014; 30:1676-83. [PMID: 25475469 DOI: 10.1016/j.cjca.2014.09.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 09/30/2014] [Accepted: 09/30/2014] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Calcific aortic valve disease affects 10%-15% of the elderly population, causing considerable morbidity and mortality. There is no imaging technique that allows for the assessment of tissue composition of the valve in vivo. We thus investigated whether multiparametric magnetic resonance imaging (MRI) could characterize and quantify lipid, fibrous, and mineralized tissues within aortic valve (AV) cusps. METHODS AV leaflets were explanted from patients with severe aortic stenosis at the time of valve replacement surgery. Aortic cusps were imaged ex vivo using 1.5 T MRI using 3 gradient-echo sequences with T1, moderate T2, and proton density weightings (T1w, T2w, and PDw). Histopathologic analysis was performed on coregistered slices to identify and measure mineralized tissue, fibrous tissue, and lipid-rich tissue. Area and mean grey values were measured in all 3 weightings by standardized software. RESULTS Four hundred ninety-two regions of interest from 30 AV leaflets were studied. Total leaflet surface and the areas of mineralized (P < 0.0001), fibrous (P = 0.002), and lipid-rich (P = 0.0001) tissues measured by MRI matched closely those measured by histopathologic examination. All 3 weightings provided significant discrimination between median grey values for mineralized, fibrous, and lipid-rich tissues (P < 0.0001 for T1w, moderate T2w, and PDw). A best-fit equation integrating the grey value data from all 3 weightings allowed multiparametric MRI to identify valve leaflet components with areas under the receiver operating characteristic curve of 0.92, 0.81, and 0.72, respectively. CONCLUSIONS AV leaflet characteristics, including tissue composition, distribution, and area, may be successfully measured by multiparametric MRI with good to excellent accuracy.
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Affiliation(s)
- Florent Le Ven
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada
| | - Helena Tizón-Marcos
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada
| | - Christina Fuchs
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada
| | - Patrick Mathieu
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada
| | - Philippe Pibarot
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada
| | - Eric Larose
- Département Multidisciplinaire De Cardiologie, Institut Universitaire de Cardiologie et de pneumologie de Québec, and Faculté de Médecine de l'Université Laval, Québec, Québec, Canada.
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Milin AC, Vorobiof G, Aksoy O, Ardehali R. Insights into aortic sclerosis and its relationship with coronary artery disease. J Am Heart Assoc 2014; 3:e001111. [PMID: 25193296 PMCID: PMC4323780 DOI: 10.1161/jaha.114.001111] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Alexandra C Milin
- Department of Internal Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Gabriel Vorobiof
- Department of Internal Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Olcay Aksoy
- Department of Internal Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Reza Ardehali
- Department of Internal Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA
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Emren ZY, Emren SV, Kılıçaslan B, Solmaz H, Susam İ, Sayın A, Abud B, Aydın M, Bayturan Ö. Evaluation of the prevalence of coronary artery disease in patients with valvular heart disease. J Cardiothorac Surg 2014; 9:153. [PMID: 25179559 PMCID: PMC4176870 DOI: 10.1186/s13019-014-0153-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 08/18/2014] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVES The aim of the present study was to retrospectively evaluate the prevalence of concurrent coronary artery disease in patients who underwent surgery due to severe valvular heart disease. The study also investigated the association of coronary artery disease with the type of valvular heart disease. MATERIALS AND METHODS A total of 241 patients (123 females [51%]), who had underwent single valvular heart surgery, were included in the study. The patients who underwent valve replacement surgery were divided into four groups: patients with severe mitral stenosis (MS), patients with severe mitral regurgitation (MR), patients with severe aortic regurgitation (AR), and patients with severe aortic stenosis (AS). Age, DM, HT, history of smoking, and LDL values were recorded as the risk factors for CAD. RESULTS Coronary artery disease was detected in 26.4% of patients with mitral stenosis and 57.7% of patients with aortic stenosis. Of the patients with mitral insufficiency, 41.9% had CAD, and 44.4% of the patients with aortic insufficiency had CAD. CONCLUSION The comparison of MS and AS groups revealed significantly higher prevalence of CAD in the AS group. There was no statistically significant difference between the MR and AR groups in terms of the prevalence of CAD. The comparison of MS and MR groups revealed significantly higher prevalence of CAD in the MR group. Furthermore, the comparison of these groups in terms of the extensiveness of the coronary artery disease revealed significantly higher Gensini score in the MR group.
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Affiliation(s)
- Zeynep Yapan Emren
- />Cardiology Department, Sandıklı State Hospital, Afyonkarahisar, Turkey
| | - Sadık Volkan Emren
- />Cardiology Department, Izmir Katip Celebi University, Ataturk Research and Training Hospital, İzmir, Turkey
| | - Barış Kılıçaslan
- />Cardiology Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - Hatice Solmaz
- />Cardiology Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - İbrahim Susam
- />Cardiology Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - Ahmet Sayın
- />Cardiology Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - Burçin Abud
- />Cardiovascular surgery Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - Mehmet Aydın
- />Cardiology Department, Izmir Tepecik Research and Training Hospital, İzmir, Turkey
| | - Özgür Bayturan
- />Cardiology Department, Manisa Celal Bayar University, Medical Faculty Hafsa Sultan Research Hospital, Manisa, Turkey
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Abstract
Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. Therefore, we discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.
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Affiliation(s)
- Joshua D Hutcheson
- Center for Interdisciplinary Cardiovascular Sciences, 3 Blackfan Circle, 17th Floor, Center for Life Sciences Boston, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Elena Aikawa
- Center for Excellence in Vascular Biology, 3 Blackfan Circle, 17th Floor, Center for Life Sciences Boston, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - W David Merryman
- Department of Biomedical Engineering, 2213 Garland Avenue, Vanderbilt University, Nashville, TN 37212, USA
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Avci A, Elnur A, Göksel A, Serdar F, Servet I, Atilla K, Mustafa TM, Cuneyt T, Yeliz G, Mustafa B, Metin EA. The relationship between neutrophil/lymphocyte ratio and calcific aortic stenosis. Echocardiography 2014; 31:1031-5. [PMID: 24528173 DOI: 10.1111/echo.12534] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The role of inflammation in fibrotic and calcific processes of atherosclerosis and aortic stenosis (AS) is similar. Furthermore, a relationship between systemic inflammation and heart failure has been well demonstrated. Recently, neutrophil/lymphocyte ratio (NLR) has been proposed as a predictive marker of systemic inflammation. We investigated the association of NLR with the severity of calcific AS and left ventricular (LV) systolic dysfunction in patients with severe calcific AS. METHODS A total of 96 patients with calcific AS were included in this retrospective study from 2011 to 2013. The severity of AS was graded according to the transaortic mean pressure gradient. The patients were divided into 3 groups as mild-to-moderate AS, severe AS with normal left ventricular ejection fraction (LVEF), and severe AS with reduced LVEF (mean gradient >40 mmHg and LVEF <50%). RESULTS Neutrophil/lymphocyte ratio was significantly higher in severe calcific AS with reduced LVEF group than the other 2 groups (3.94 ± 0.88, P < 0.001). In addition, NLR was higher in severe AS with normal LVEF group than mild-to-moderate AS group (2.69 ± 1.00 vs. 2.05 ± 0.64, P = 0.008). There was a statistically significant correlation between NLR and both transaortic mean pressure gradient and aortic valve peak velocity in patients with mild-to-severe AS with normal LVEF (n = 81; r = 0.369, P < 0.001; r = 0.290, P = 0.004; respectively). CONCLUSION Increased NLR is related to the severity of calcific AS and LV systolic dysfunction in patients with severe calcific AS.
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Affiliation(s)
- Anil Avci
- Cardiology Deparment, Kartal Koşuyolu Heart Research and Training Hospital, Istanbul, Turkey
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De Vecchis R, Di Biase G, Esposito C, Ciccarelli A, Cioppa C, Giasi A, Ariano C, Cantatrione S. Statin use for nonrheumatic calcific aortic valve stenosis: a review with meta-analysis. J Cardiovasc Med (Hagerstown) 2014; 14:559-67. [PMID: 23032960 DOI: 10.2459/jcm.0b013e3283587267] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
AIMS To synthesize by meta-analysis the findings of recent experimental studies focusing on possible therapeutic effectiveness of statins for nonrheumatic calcific aortic stenosis. METHODS Observational studies and randomized controlled trials (RCTs) were selected from the Pubmed database to evaluate the hemodynamic progression of aortic stenosis in statin-treated patients compared with controls (i.e. patients with aortic stenosis taking placebo or no treatment). The endpoints were the annualized changes in one or more of the following ultrasonographic measurements: peak aortic valve jet velocity, peak aortic valve pressure gradient, mean aortic valve pressure gradient aortic valve area (AVA). For estimating the overall effect of statin therapy on each of the above-mentioned continuous variables across the considered studies, we used the weighted mean difference (WMD) as effect size measure. In addition, we calculated the odds of aortic valve replacement surgery and cardiovascular death in both statin-treated patients and controls for subsequently estimating the appropriate odds ratios. RESULTS Nine studies were selected. A lower annualized increase in peak aortic valve jet velocity was found in statin-treated patients compared with controls (overall WMD: -0.09 m/s per year, 95% CI -0.16, -0.01 P = 0.018). Similarly, a smaller annualized increase in peak aortic valve pressure gradient was found in the statin group (overall WMD: -2.04 mmHg/year 95% CI: -3.56, -0.52, P = 0.0085). However, the overall effects in statin-treated patients on both annualized increases in mean aortic valve pressure gradient and decreases in AVA were not significantly different from those found in controls. Moreover, there was no significant difference in cardiovascular outcomes in the statin groups compared with placebo groups in each of the three analyzed RCTs and overall. CONCLUSION Significant benefit of statin therapy in retarding hemodynamic deterioration was identified by favorable effects concerning annualized changes in peak aortic valve jet velocity and peak aortic valve pressure gradient; on the contrary, in statin-treated patients with aortic stenosis, no significant improvement was found for annualized changes in mean aortic valve pressure gradient and AVA and clinical outcomes.
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Affiliation(s)
- Renato De Vecchis
- Cardiology Unit, Presidio Sanitario Intermedio Elena d'Aosta, Napoli, Italy.
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Abstract
Aortic stenosis is the most commonly encountered valvular disease in the elderly, with approximately 2-3% of individuals over 65 years of age afflicted. The most common cause of acquired aortic stenosis is calcific degeneration, characterized by a slowly progressive, asymptomatic period which can last decades. Once symptomatic, the clinical manifestation of aortic stenosis is from functional obstruction of left ventricular outflow and the additional hemodynamic effects on the left ventricle and vasculature. With advances in echocardiography, individuals with aortic stenosis are increasingly diagnosed in the asymptomatic latent period. However, echocardiographic measures alone cannot identify clinically significant outflow obstruction as there is considerable overlap in hemodynamic severity between symptomatic and asymptomatic individuals. Current clinical guidelines predicate the timing of surgical valve replacement on the presence or absence of symptoms. Management for symptomatic, significant stenosis is surgical valve replacement as there are no current medical therapies reliably proven to decrease aortic stenosis severity or improve long-term outcomes. However, recent retrospective studies have demonstrated an association between atherosclerotic disease risk factors, such as hyperlipidemia and aortic stenosis. Given these findings, there are now advocates for prospective primary prevention trials for aortic stenosis in patients with mild or moderate valvular disease. The following paper will discuss etiology, diagnostic evaluation and therapeutic options of acquired aortic stenosis. This review will discuss etiology, diagnostic evaluation, and therapeutic options of acquired aortic stenosis.
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Affiliation(s)
- Rosario V Freeman
- Division of Cardiology, University of Washington, Seattle 98109, USA.
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