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Personalized medicine is an emerging concept involving managing the health of patients based on their individual characteristics, including particular genotypes. Cardiovascular diseases are heritable traits, and family history information is useful for risk prediction. As such, determining genetic information (germline genetic mutations) may also be applied to risk prediction. Furthermore, accumulating evidence suggests that genetic background can provide guidance for selecting effective treatments and preventive strategies in individuals with particular genotypes. These concepts may be applicable both to rare Mendelian diseases and to common complex traits. In this review, we define the concept and provide examples of personalized medicine based on human genetics for cardiovascular diseases, including coronary artery disease, arrhythmia, and cardiomyopathies. We also provide a particular focus on Mendelian randomization studies, especially those examining loss-of function genetic variations, for identifying high-risk individuals, as well as signaling pathways that may be useful targets for improving healthy living without cardiovascular events.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRS ) using a genome-wide association study summary statistic from the BioBank Japan Project. We assessed the association of PRS with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRS was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10 ). PRS was also significantly linked to LDL-C in controls (p trend = 3.6 × 10 ) but not in FH patients. Moreover, we could not detect any association between PRS and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRS than controls. However, PRS may have little additional effect on LDL-C and CAD among FH patients.

The Effect of Diet on Cardiovascular Disease, Heart Disease, and Blood Vessels [...]

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype–phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Data of patients with FH (N = 1050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P  = 1.2 × 10 −5 ). The event rates per 1000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.

Background Use of ezetimibe on top of statin therapy has been shown to be effective to reduce LDL cholesterol level in hypercholesterolemic patients. However, little is known regarding the individual variety of the effectiveness of ezetimibe. We hypothesized that hypercholesterolemic patients with a mutation in ABCG5 or ABCG8 gene exhibit better response to ezetimibe than those without, based on the fact that ezetimibe is hyper-effective for in patients with sitosterolemia caused by ABCG5 or ABCG8 genetic mutations. Methods Electronical medical record were reviewed in a total of 321 hypercholesterolemic patients (baseline LDL cholesterol = 192 ± 46 mg/dl) prescribed ezetimibe 10 mg daily on top of atorvastatin 10 mg daily who had undergone genetic analysis of ABCG5 or ABCG8 gene in our institute since 2006 to 2017. Pathogenicity of the variants were determined using standard variant filtering schema, including minor allele frequency, in silico annotation tools. Patients were divided into 2 groups based on the presence of ABCG5 or ABCG8 mutation. We compared the percent reduction of LDL cholesterol as well as the achieved LDL cholesterol levels between these 2 groups. Results We found 26 (8%) individuals who exhibit deleterious mutations in ABCG5 or ABCG8 gene. Baseline characteristics under the atorvastatin 10 mg therapy were comparable in age, gender, and LDL cholesterol level between 2 groups. Under these conditions, percent reduction of LDL cholesterol in mutation positive group was significantly larger than that of mutation negative group (28 ± 16% vs. 39 ± 21%, p  < 0.05). As a result, the achieved LDL cholesterol level in mutation positive group was significantly lower than that of mutation negative group (87 ± 29 mg/dl vs. 72 ± 26% mg/dl, p  < 0.05). Conclusion These results suggest that ezetimibe-atorvastatin combination therapy might be more beneficial in hypercholesterolemic patients with a mutation in ABCG5 or ABCG8 gene.