Genetics of cardiovascular disease

Alternative splicing determines which exons are included in mature RNA and accounts for the majority of transcriptomic diversity. In this Review, Gotthardt and colleagues discuss how alternative splicing is regulated in the heart and how it differs in cardiac development, physiological adaptation and pathological remodelling. They also summarize technological advances in the field and potential applications of splicing data in cardiovascular medicine.

Advances in machine learning technology in the past decade have accelerated the discovery of genetic loci associated with aortic disease. In this Review, Lindsay and colleagues discuss how emerging insights into the genetic architecture of aortic disease can improve the accuracy of disease prediction and facilitate the discovery of new therapeutic targets.

Transthyretin amyloidosis is a progressive, life-threatening disease caused by the accumulation of misfolded transthyretin, predominantly in the nerves and heart. In this Review, Aimo and colleagues provide an update on the treatment strategies aimed at blocking transthyretin production, including small interfering RNAs, antisense oligonucleotides and gene editing approaches.

In this Review, Klarin and Natarajan discuss the implementation of polygenic risk scores in clinical medicine for risk prediction and screening algorithms for coronary artery disease, prioritization of patient subgroups that are likely to derive benefit from treatment, and efficient prospective clinical trial designs.

In this Review, Walsh et al. explore the complex contribution of genes encoding non-sarcomeric proteins that are robustly associated with non-syndromic or isolated hypertrophic cardiomyopathy to the genetics of cardiomyopathies across the full range of variant classes, from common regulatory variants to complete gene knockouts.

In this Review, Foo and colleagues summarize the benchmark studies that have mapped the role of enhancers in cardiac disease and development, highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis and consider how enhancer targeting might soon be developed for heart disease.

In this Review, Seidman and colleagues summarize the progress over the past 10 years with regard to genomic discoveries and strategies at the forefront of research on congenital heart disease (CHD), highlighting definitive and candidate genes associated with CHD in humans and the potential of integrating technological advances to gain new insights into the genetic architecture of CHD.

Epidemiological studies indicate a genetic component to the risk of sudden cardiac death (SCD). In this Review, Behr and colleagues evaluate monogenic and polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy and analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.

In this Review, Holmes and colleagues compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits and explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.

In this Review, Entcheva and Kay discuss a decade of important developments and applications of optogenetics to the heart, focusing on near-term and longer-term clinical translation of this technology in cardiology.

In this Review, Padmanabhan and Dominiczak discuss how genomics has transformed our understanding of blood pressure regulation and hypertension, summarizing the current knowledge of blood pressure genomics and highlighting the opportunities and challenges for drug repurposing and pharmacogenomics for the treatment of hypertension.

Clonal haematopoiesis of indeterminate potential (CHIP) commonly occurs as a result of mutations in transcriptional regulators and is associated with a doubling of the risk of atherosclerotic cardiovascular disease. Jaiswal and Libby propose that CHIP contributes to the increased inflammation seen in ageing and thereby explains some of the age-related risk of cardiovascular disease.

In this Review, Rosenbaum and colleagues give a broad perspective on the genetic causes of dilated cardiomyopathy to provide a context for a discussion of the pragmatic use of genetic testing in heart failure clinics for patients presenting with new-onset dilated cardiomyopathy.

This Review summarizes the role of transcription factors and epigenetic remodelling in modulating macrophage plasticity, provides an overview of the cooperative action of transcription factors and epigenetic modifiers controlling macrophage activation in the context of atherosclerosis and inflammation, and highlights the therapeutic potential of modulating transcription factor activity.

Rheumatic heart disease is a complication of group A streptococcal infection and rheumatic fever. In this Review, Muhamed and colleagues assess the emerging role of genome-wide association studies in detecting loci associated with genetic susceptibility to rheumatic heart disease.

Pulmonary arterial hypertension (PAH) is characterized by right ventricular hypertrophy and the absence of underlying cardiac or pulmonary disease. In this Review, Southgate and colleagues discuss the latest advances in the identification of genetic variants underlying PAH development and progression.

With the increase in the availability of RNA screening tools, numerous non-coding RNAs with important functions in the heart have been identified. In this Review, Lu and Thum discuss the non-coding RNA candidates with diagnostic and therapeutic potential in cardiovascular disease.

Circular RNAs (circRNAs) are emerging as a new class of non-coding RNA molecules. In this Review, the authors discuss the current understanding of circRNA biogenesis and function, with a particular emphasis on the cardiovascular system.

In this Review, the authors summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. They also discuss the use of systems modelling to discover new therapies to target mechanosignalling in heart disease.

Familial hypercholesterolaemia (FH) is the most commonly encountered genetic condition that predisposes to premature cardiovascular disease. In this Review, Berberich and Hegele revisit the genetic complexity of FH and discuss our revised understanding of the mechanisms of FH and the implications for screening, diagnosis, and patient management.

Novel antisense oligonucleotide and small interfering RNA technology can be used to reduce levels of lipoproteins that cause cardiovascular disease. In this Review, Nordestgaard and colleagues describe the principles of these gene-silencing approaches and summarize the trials that have tested the efficacy of these approaches in patients at risk of cardiovascular disease.

In this Review, Christoffels and colleagues detail the transcriptional networks that control development and homeostasis of the cardiac conduction system. The pathophysiological consequences of aberrations in these networks are also discussed, with potential insights into the generation of biological pacemakers.

Genotype-guided selection of oral P2Y₁₂ inhibitor therapy (clopidogrel versus prasugrel or ticagrelor) can reduce the incidence of bleeding in patients who have undergone primary percutaneous coronary intervention.

The transfer of the longevity-associated variant of BPIFB4 to Apoe^–/– mice fed a high-fat diet via gene therapy halted plaque formation and reduced inflammation.

Cardiomyocyte-selective gene therapy to inhibit calcium/calmodulin-dependent protein kinase II effectively suppresses ventricular arrhythmias in mice with mutations known to cause catecholaminergic polymorphic ventricular tachycardia.

Patients with chemotherapy-induced cardiomyopathy have a high prevalence of rare variants of cardiomyopathy-related genes, in particular titin-truncating variants.

A novel bioelectronic system that combines automated arrhythmia detection with optogenetic engineering for arrhythmia termination is able to stop atrial fibrillation without the need of electrical shock in a closed-chest experimental model.

Precision cardiology is a vision of a health-care approach that identifies the optimal course of care for each patient. Although precision cardiology is still in its nascent stage, new approaches and methodologies are being developed to achieve this goal and to overcome technical and implementation barriers. In 2018, several high-impact studies made progress in this direction.