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Cardiovascular Genetics
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Cardiovascular Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (18 December 2020) | Viewed by 55103

Special Issue Editors

Dr. Andreas Brodehl

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Guest Editor
Heart and Diabetes Centre NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Interests: genetic cardiomyopathies; ARVC; DCM; RCM; cardiovascular biochemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hendrik Milting

E-Mail Website
Guest Editor
Heart and Diabetes Centre NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Interests: molecular and cellular pathomechanism of cardiomyopathies
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Brenda Gerull

E-Mail Website
Guest Editor
Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, D-97080 Würzburg, Germany
Interests: clinical and molecular genetics of cardiomyopathies; genetic diagnostics; molecular and cellular mechanisms; therapy in pre-clinical model systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over thirty years ago, the first pathogenic mutation in MYH7, encoding the myosin heavy chain associated with hypertrophic cardiomyopathy was described. Since the beginnings of cardiovascular genetics, it became evident in thousands of clinical cases that many cardiomyopathies—channelopathies as well as complex multi-genetic diseases like coronary artery disease—have a genetic etiology. The development of next-generation sequencing techniques led to an impressive gain of genetic insights into cardiovascular diseases during the last several decades. However, the increasing number of different genes and mutations involved in cardiomyopathies and channelopathies as well as the complexity of polygenic cardiovascular diseases cause novel challenges in research and in clinical practice. Technical progress in genomics, bioinformatics, as well as genome editing lead to remarkable molecular insights and translational aspects in the context of personalized medicine. Novel animal and cell culture models like cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) contribute to important discoveries in cardiovascular genetics.
In summary, the aim of this Special Issue entitled “Cardiovascular Genetics” is to present state-of-the art review articles summarizing trends within the scientific community as well as to publish original articles providing novel molecular insights into genetic or genomic aspects of cardiovascular diseases. Especially, studies with a focus on translational research or the development of suitable gene-specific therapies for cardiovascular diseases are highly welcome.

Dr. Andreas Brodehl
Prof. Dr. Hendrik Milting
Prof. Dr. Brenda Gerull
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiovascular genetics
  • cardiomyopathies
  • channelopathies
  • heart failure
  • coronary artery disease
  • gene therapy

Published Papers (16 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 193 KiB  
Editorial
Special Issue “Cardiovascular Genetics”
by Andreas Brodehl, Hendrik Milting and Brenda Gerull
Genes 2021, 12(4), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040479 - 26 Mar 2021
Cited by 1 | Viewed by 1631
Abstract
Since the beginnings of cardiovascular genetics, it became evident in thousands of clinical cases that many cardiomyopathies, channelopathies, aortopathies as well as complex multifactorial diseases such as coronary artery disease, atherosclerosis or atrial fibrillation (AF) have a genetic etiology [...] Full article
(This article belongs to the Special Issue Cardiovascular Genetics)

Research

Jump to: Editorial, Review, Other

13 pages, 1877 KiB  
Article
The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy
by Olga Kulikova, Andreas Brodehl, Anna Kiseleva, Roman Myasnikov, Alexey Meshkov, Caroline Stanasiuk, Anna Gärtner, Mikhail Divashuk, Evgeniia Sotnikova, Sergey Koretskiy, Maria Kharlap, Viktoria Kozlova, Elena Mershina, Polina Pilus, Valentin Sinitsyn, Hendrik Milting, Sergey Boytsov and Oxana Drapkina
Genes 2021, 12(1), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010121 - 19 Jan 2021
Cited by 23 | Viewed by 3765
Abstract
Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing [...] Read more.
Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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17 pages, 1669 KiB  
Article
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia
by Alexey Meshkov, Alexandra Ershova, Anna Kiseleva, Evgenia Zotova, Evgeniia Sotnikova, Anna Petukhova, Anastasia Zharikova, Pavel Malyshev, Tatyana Rozhkova, Anastasia Blokhina, Alena Limonova, Vasily Ramensky, Mikhail Divashuk, Zukhra Khasanova, Anna Bukaeva, Olga Kurilova, Olga Skirko, Maria Pokrovskaya, Valeriya Mikova, Ekaterina Snigir, Alexsandra Akinshina, Sergey Mitrofanov, Daria Kashtanova, Valentin Makarov, Valeriy Kukharchuk, Sergey Boytsov, Sergey Yudin and Oxana Drapkinaadd Show full author list remove Hide full author list
Genes 2021, 12(1), 66; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010066 - 06 Jan 2021
Cited by 31 | Viewed by 6048
Abstract
Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics [...] Read more.
Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995–2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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18 pages, 13804 KiB  
Article
Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults—The Value of Reevaluating and Expanding Gene Panel Analyses
by Eva Fernlund, Antheia Kissopoulou, Henrik Green, Jan-Erik Karlsson, Rada Ellegård, Hanna Klang Årstrand, Jon Jonasson and Cecilia Gunnarsson
Genes 2020, 11(12), 1472; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121472 - 08 Dec 2020
Cited by 10 | Viewed by 3535
Abstract
Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial [...] Read more.
Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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17 pages, 934 KiB  
Article
Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes
by Katharina Sielemann, Zaher Elbeck, Anna Gärtner, Andreas Brodehl, Caroline Stanasiuk, Henrik Fox, Lech Paluszkiewicz, Jens Tiesmeier, Stefan Wlost, Jan Gummert, Stefan P. Albaum, Janik Sielemann, Ralph Knöll and Hendrik Milting
Genes 2020, 11(12), 1430; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121430 - 28 Nov 2020
Cited by 8 | Viewed by 2602
Abstract
Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we [...] Read more.
Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we distinguished four different genetic cardiomyopathies based on gene expression signatures. In this study, RNA-Sequencing was used to identify gene expression signatures in myocardial tissue of cardiomyopathy patients in comparison to non-failing human hearts. Therefore, expression differences between patients with specific affected genes, namely LMNA (lamin A/C), RBM20 (RNA binding motif protein 20), TTN (titin) and PKP2 (plakophilin 2) were investigated. We identified genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies. Some regulated pathways are common between patients with mutations in RBM20 and TTN as the splice factor RBM20 targets amongst other genes TTN, leading to a similar response on pathway level, even though many differentially expressed genes (DEGs) still differ between both sample types. The myocardium of patients with mutations in LMNA is widely associated with upregulated genes/pathways involved in immune response, whereas mutations in PKP2 lead to a downregulation of genes of the extracellular matrix. Our results contribute to further understanding of the underlying molecular pathomechanisms aiming for novel and better treatment of genetic cardiomyopathies. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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6 pages, 200 KiB  
Article
The Erythropoetin rs1617640 Gene Polymorphism Associates with Hemoglobin Levels, Hematocrit and Red Blood Cell Count in Patients with Peripheral Arterial Disease
by Wilfried Renner, Melanie Kaiser, Sebastian Khuen, Olivia Trummer, Harald Mangge and Tanja Langsenlehner
Genes 2020, 11(11), 1305; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111305 - 04 Nov 2020
Cited by 4 | Viewed by 2174
Abstract
Background: Erythropoietin has a pivotal role in erythropoiesis and angiogenesis. A common polymorphism (rs1617640, A > C) in the promoter of the erythropoietin gene (EPO) has been associated with erythropoietin expression and microvascular complications of diabetes. We aimed to analyze the potential role [...] Read more.
Background: Erythropoietin has a pivotal role in erythropoiesis and angiogenesis. A common polymorphism (rs1617640, A > C) in the promoter of the erythropoietin gene (EPO) has been associated with erythropoietin expression and microvascular complications of diabetes. We aimed to analyze the potential role of this polymorphism in the pathogenesis of peripheral arterial disease (PAD). Methods: EPO genotypes and laboratory markers for erythropoiesis were determined in 945 patients with PAD. Results: The minor EPO rs1617640 C-allele was associated in an allele-dose-dependent manner with hemoglobin levels (p = 0.006), hematocrit (p = 0.029), and red blood cell count (p = 0.003). In a multivariate linear regression analysis including conventional risk factors diabetes, sex, and smoking, EPO genotypes were furthermore associated with age at onset of PAD symptoms (p = 0.009). Conclusions: The EPO rs1617640 gene polymorphism affects erythropoiesis, leads to an earlier onset of PAD, and is a potential biomarker for the pathogenesis of this disease. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
11 pages, 274 KiB  
Article
Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study
by Luigi Castaldo, Federica Laguzzi, Rona J. Strawbridge, Damiano Baldassarre, Fabrizio Veglia, Lorenzo Vigo, Elena Tremoli, Ulf de Faire, Per Eriksson, Andries J. Smit, Jiri Aubrecht, Karin Leander, Matteo Pirro, Philippe Giral, Alberto Ritieni, Giovanni Di Minno, Anders Mälarstig and Bruna Gigante
Genes 2020, 11(11), 1243; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111243 - 22 Oct 2020
Cited by 5 | Viewed by 2304
Abstract
Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study (n = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels (p < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMTmax and c-IMTmean-max (p = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
13 pages, 3164 KiB  
Article
Exaggerated Autophagy in Stanford Type A Aortic Dissection: A Transcriptome Pilot Analysis of Human Ascending Aortic Tissues
by Zeyi Zhou, Yan Liu, Xiyu Zhu, Xinlong Tang, Yali Wang, Junxia Wang, Can Xu, Dongjin Wang, Jie Du and Qing Zhou
Genes 2020, 11(10), 1187; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101187 - 13 Oct 2020
Cited by 19 | Viewed by 2820
Abstract
Stanford type A aortic dissection (TAAD) is one of the most dangerous diseases of acute aortic syndrome. Molecular pathological studies on TAAD can aid in understanding the disease comprehensively and can provide insights into new diagnostic markers and potential therapeutic targets. In this [...] Read more.
Stanford type A aortic dissection (TAAD) is one of the most dangerous diseases of acute aortic syndrome. Molecular pathological studies on TAAD can aid in understanding the disease comprehensively and can provide insights into new diagnostic markers and potential therapeutic targets. In this study, we defined the molecular pathology of TAAD by performing transcriptome sequencing of human ascending aortic tissues. Pathway analysis revealed that activated inflammation, cell death and smooth muscle cell degeneration are the main pathological changes in aortic dissection. However, autophagy is considered to be one of the most important biological processes, regulating inflammatory reactions and degenerative changes. Therefore, we focused on the pathological role of autophagy in aortic dissection and identified 10 autophagy-regulated hub genes, which are all upregulated in TAAD. These results indicate that exaggerated autophagy participates in the pathological process of aortic dissection and may provide new insight for further basic research on TAAD. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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11 pages, 671 KiB  
Article
CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation
by Stefan Cristian Vesa, Sonia Irina Vlaicu, Vitalie Vacaras, Sorin Crisan, Octavia Sabin, Sergiu Pasca, Adrian Pavel Trifa, Tamas Rusz-Fogarasi, Madalina Sava and Anca Dana Buzoianu
Genes 2020, 11(7), 822; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11070822 - 20 Jul 2020
Cited by 6 | Viewed by 2536
Abstract
Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of [...] Read more.
Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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18 pages, 9497 KiB  
Article
Transcriptional Profiling of Normal, Stenotic, and Regurgitant Human Aortic Valves
by Christina L. Greene, Kevin J. Jaatinen, Hanjay Wang, Tiffany K. Koyano, Mary S. Bilbao and Y. Joseph Woo
Genes 2020, 11(7), 789; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11070789 - 14 Jul 2020
Cited by 16 | Viewed by 3291
Abstract
The genetic mechanisms underlying aortic stenosis (AS) and aortic insufficiency (AI) disease progression remain unclear. We hypothesized that normal aortic valves and those with AS or AI all exhibit unique transcriptional profiles. Normal control (NC) aortic valves were collected from non-matched donor hearts [...] Read more.
The genetic mechanisms underlying aortic stenosis (AS) and aortic insufficiency (AI) disease progression remain unclear. We hypothesized that normal aortic valves and those with AS or AI all exhibit unique transcriptional profiles. Normal control (NC) aortic valves were collected from non-matched donor hearts that were otherwise acceptable for transplantation (n = 5). Valves with AS or AI (n = 5, each) were collected from patients undergoing surgical aortic valve replacement. High-throughput sequencing of total RNA revealed 6438 differentially expressed genes (DEGs) for AS vs. NC, 4994 DEGs for AI vs. NC, and 2771 DEGs for AS vs. AI. Among 21 DEGs of interest, APCDD1L, CDH6, COL10A1, HBB, IBSP, KRT14, PLEKHS1, PRSS35, and TDO2 were upregulated in both AS and AI compared to NC, whereas ALDH1L1, EPHB1, GPX3, HIF3A, and KCNT1 were downregulated in both AS and AI (p < 0.05). COL11A1, H19, HIF1A, KCNJ6, PRND, and SPP1 were upregulated only in AS, and NPY was downregulated only in AS (p < 0.05). The functional network for AS clustered around ion regulation, immune regulation, and lipid homeostasis, and that for AI clustered around ERK1/2 regulation. Overall, we report transcriptional profiling data for normal human aortic valves from non-matched donor hearts that were acceptable for transplantation and demonstrated that valves with AS and AI possess unique genetic signatures. These data create a roadmap for the development of novel therapeutics to treat AS and AI. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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11 pages, 279 KiB  
Article
Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients
by Adela-Nicoleta Roşian, Ştefan Horia Roşian, Bela Kiss, Maria Georgia Ştefan, Adrian Pavel Trifa, Camelia Diana Ober, Ovidiu Anchidin and Anca Dana Buzoianu
Genes 2020, 11(4), 438; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040438 - 17 Apr 2020
Cited by 17 | Viewed by 2273
Abstract
(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The ABCB1 genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban’s plasma level [...] Read more.
(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The ABCB1 genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban’s plasma level and to establish if a certain relationship has clinical relevance. (2) Methods: Fifty-three NVAF patients were treated with 5 mg apixaban twice/day (70.0 years, range: 65–77, 60.4% men). Trough and peak plasma concentrations of apixaban were determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS), and ABCB1 genotyping was performed. (3) Results: Apixaban plasma concentrations varied considerably. They were higher in women than in men (311.2 ng/dL vs. 252.2 ng/dL; p = 0.05) and were lower in patients with heart failure (149.4 ng/dL vs. 304.5 ng/dL; p < 0.01). Creatinine clearance was inversely correlated with the apixaban plasma level (Spearman correlation: r = −0.365; p = 0.007 for trough concentrations). No statistically significant differences between the genotypic groups of ABCB1 rs1045642 and ABCB1 rs4148738 were found in the trough or peak apixaban plasma concentrations. (4) Conclusions: Pharmacokinetic parameters are influenced by several clinical factors of which renal function is the major determinant. Plasma concentrations measured in women had higher values than those measured in men, and heart failure was associated with decreased plasma levels of apixaban. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)

Review

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44 pages, 9690 KiB  
Review
Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies
by Tyler J. Creamer, Emily E. Bramel and Elena Gallo MacFarlane
Genes 2021, 12(2), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020183 - 27 Jan 2021
Cited by 27 | Viewed by 5538
Abstract
Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain [...] Read more.
Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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14 pages, 1700 KiB  
Review
Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications
by Timothy F. Spracklen, Graham Chakafana, Peter J. Schwartz, Maria-Christina Kotta, Gasnat Shaboodien, Ntobeko A. B. Ntusi and Karen Sliwa
Genes 2021, 12(1), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010103 - 15 Jan 2021
Cited by 15 | Viewed by 5171
Abstract
Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In [...] Read more.
Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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16 pages, 267 KiB  
Review
Genetic Variants behind Cardiovascular Diseases and Dementia
by Wei-Min Ho, Yah-Yuan Wu and Yi-Chun Chen
Genes 2020, 11(12), 1514; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121514 - 18 Dec 2020
Cited by 7 | Viewed by 3416
Abstract
Cardiovascular diseases (CVDs) and dementia are the leading causes of disability and mortality. Genetic connections between cardiovascular risk factors and dementia have not been elucidated. We conducted a scoping review and pathway analysis to reveal the genetic associations underlying both CVDs and dementia. [...] Read more.
Cardiovascular diseases (CVDs) and dementia are the leading causes of disability and mortality. Genetic connections between cardiovascular risk factors and dementia have not been elucidated. We conducted a scoping review and pathway analysis to reveal the genetic associations underlying both CVDs and dementia. In the PubMed database, literature was searched using keywords associated with diabetes mellitus, hypertension, dyslipidemia, white matter hyperintensities, cerebral microbleeds, and covert infarctions. Gene lists were extracted from these publications to identify shared genes and pathways for each group. This included high penetrance genes and single nucleotide polymorphisms (SNPs) identified through genome wide association studies. Most risk SNPs to both diabetes and dementia participate in the phospholipase C enzyme system and the downstream nositol 1,4,5-trisphosphate and diacylglycerol activities. Interestingly, AP-2 (TFAP2) transcription factor family and metabolism of vitamins and cofactors were associated with genetic variants that were shared by white matter hyperintensities and dementia, and by microbleeds and dementia. Variants shared by covert infarctions and dementia were related to VEGF ligand–receptor interactions and anti-inflammatory cytokine pathways. Our review sheds light on future investigations into the causative relationships behind CVDs and dementia, and can be a paradigm of the identification of dementia treatments. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)

Other

6 pages, 782 KiB  
Case Report
RBM20-Associated Ventricular Arrhythmias in a Patient with Structurally Normal Heart
by Yuriy Vakhrushev, Alexandra Kozyreva, Andrey Semenov, Polina Sokolnikova, Tamara Lubimtseva, Dmitry Lebedev, Natalia Smolina, Sergey Zhuk, Lubov Mitrofanova, Elena Vasichkina and Anna Kostareva
Genes 2021, 12(1), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010094 - 13 Jan 2021
Cited by 6 | Viewed by 2424
Abstract
RBM20 (RNA-binding motif protein 20) is a splicing factor targeting multiple cardiac genes, and its mutations cause cardiomyopathies. Originally, RBM20 mutations were discovered to cause the development of dilated cardiomyopathy by erroneous splicing of the gene TTN (titin). Titin is a giant protein [...] Read more.
RBM20 (RNA-binding motif protein 20) is a splicing factor targeting multiple cardiac genes, and its mutations cause cardiomyopathies. Originally, RBM20 mutations were discovered to cause the development of dilated cardiomyopathy by erroneous splicing of the gene TTN (titin). Titin is a giant protein found in a structure of the sarcomere that functions as a molecular spring and provides a passive stiffness to the cardiomyocyte. Later, RBM20 mutations were also described in association with arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Here, we present a clinical case of a rare arrhythmogenic phenotype and no structural cardiac abnormalities associated with a RBM20 genetic variant of uncertain significance. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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6 pages, 529 KiB  
Case Report
Combined PTPN11 and MYBPC3 Gene Mutations in an Adult Patient with Noonan Syndrome and Hypertrophic Cardiomyopathy
by Martina Caiazza, Marta Rubino, Emanuele Monda, Annalisa Passariello, Adelaide Fusco, Annapaola Cirillo, Augusto Esposito, Anna Pierno, Federica De Fazio, Roberta Pacileo, Eloisa Evangelista, Giuseppe Pacileo, Maria Giovanna Russo and Giuseppe Limongelli
Genes 2020, 11(8), 947; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11080947 - 17 Aug 2020
Cited by 18 | Viewed by 3973
Abstract
In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 [...] Read more.
In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM. Full article
(This article belongs to the Special Issue Cardiovascular Genetics)
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