Frontiers in precision medicine: genes and their modulation by miRNAs

Precision medicine is the vision of utilizing genetic information to discover individual disease mechanisms, better characterize patients at risk, and focus treatments and interventions on those truly in need.1 One might argue that we already do so by obtaining family history and lifestyle habits including smoking, and by measuring blood pressure, LDL-cholesterol, and plasma glucose as recommended by practice guidelines.2–4 However, it is obvious that some smokers never get a tumour or an infarct, even some with familial hypercholesterolaemia are protected from atherosclerosis, and certain diabetics never get renal failure— the so-called Helmut Schmidt or Winston Churchill syndrome. Precision medicine, among others, attempts to characterize the genetic background that determines the susceptibility or resistance to cardiovascular risk factors and eventually the propensity to develop major cardiovascular events.5 We recently learned that gene transcription and translation is modulated by a vast number of so-called microRNAs (miRNAs).6 MiRNAs have been measured in plasma in many conditions, but may be more important in critical tissues regulating metabolism, circulatory control,7 inflammatory heart disease,8 and eventually for clinical outcome.9 The liver is crucial for metabolic regulation and thus the review entitled ‘LivermicroRNAs: potential mediators and biomarkers for metabolic and cardiovascular disease?’, authored by Manuel Mayr and colleagues from the King’s College London in the UK is a timely update on the subject.10 The authors summarize the rapidly evolving knowledge about liver miRNAs, such as miR-33, -33*, -22, -30c, -144, -148a, -24, -29, and -122, and their role in hepatic lipid metabolism, metabolic syndrome, and type-2 diabetes, and in turn atherosclerosis and cardiovascular disease as well as in non-alcoholic fatty liver disease. miR-122 has the greatest potential as a biomarker as it represents the most abundant and most specific liver miRNA. miR-122 plays a central role in lipid and glucose homeostasis and is detectable in serum and plasma, and may therefore represent a novel biomarker for cardiovascular and metabolic diseases. Genetics also play an important role in coronary heart disease, but the clinical utility of genomic risk scores relative to currently used scores, such as the SCORE risk charts of the European Society of Cardiology or the Framingham Risk Score, has so far been disappointing. In a FAST TRACK manuscript ‘Genomic prediction of coronary heart disease’, Michael Inouye and colleagues from the University of Melbourne in Parkville, Australia aimed to construct and externally validate a coronary heart disease genomic risk score, in terms of lifetime coronary heart disease risk and relative to traditional clinical risk scores.5 They based their score on 49 310 single nucleotide polymorphisms (SNPs) derived from the CARDIoGRAMplusC4D Consortium meta-analysis of coronary heart disease and independently tested it using five prospective population cohorts, i.e. three FINRISK cohorts encompassing 12 676 individuals with 757 incident coronary events, and two Framingham Heart Study cohorts comprising 3406 subjects with 587 coronary events. The genomic score was strongly associated with incident coronary heart disease, with a hazard ratio of 1.74 in the FINRISK cohort and 1.28 in Framingham. Of note, its predictive value remained largely unchanged by adjustment for traditional risk factors, including family history. Integration of the genomic score with the Framingham Score or ACC/AHA13 scores improved 10-year coronary risk prediction with a C-index of 1.5–1.6%, particularly for individuals ≥60 years old where the C-index averaged 4.6–5.1%. Importantly, the genomic score captured different trajectories of absolute risk, with men in the top 20% of attaining 10% cumulative coronary risk 12–18 years earlier than those in the bottom 20%. High genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. The authors conclude that a genomic risk score based on a large number of SNPs substantially improves coronary risk prediction and encodes different trajectories of lifetime risk not captured by traditional clinical risk scores. The manuscript is accompanied by an Editorial authored by Benjamin A. Goldstein from Duke University in Durham, North Carolina, USA.11 Cumulative mortality rate (A) and mortality and/or dissection rate (B) of patients with an FBN1 mutation leading to a dominantnegative effect (red dotted line) and patients with a mutation leading to haploinsufficiency (blue line). The hazard ratios shown are adjusted for sex, age at inclusion, and the presence of aortic dissection and aortic surgery at baseline. (from Franken R, Groenink M, deWaard V, Feenstra HMA, Scholte AJ, van den Berg MP, Pals G, Zwinderman AH, Timmermans J, Mulder BJM. Genotype impacts survival in Marfan syndrome. See pages 3285–3290.) When compared with controls (black), subjects with heart failure with preserved ejection fraction (red) displayed impaired pulmonary vasodilation, with less reduction in pulmonary vascular resistance (A), greater reduction in pulmonary artery compliance (B), and steeper slope of pulmonary artery pressure-flow relationship (C). In heart failure with preserved ejection fraction subjects, pulmonary vascular resistance increased with decreasing mixed venous oxygen saturation (pulmonary artery), whereas no such relationship was observed in controls (D). (from Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. See pages 3294–3302.) Furthermore, genetic mutations can also affect large blood vessels such as the aorta.17 Romy Franken and colleagues from the Academic Medical Centre Amsterdam in The Netherlands addressed this issue in their paper ‘Genotype impacts survival in Marfan syndrome’.18 To that end, they prospectively collected clinical and genetic data from all 570 adults with Marfan syndrome who have been included in the Dutch CONCOR registry with a mean age of 37 years and followed them up for 8 years. Aortic surgery at baseline was noted in 38% of men and only in 19% of women, and during follow-up in 24% and 15%, respectively. After 10 years, survival was 93.8% and dissection-free survival 84.2%. A pathogenic FBN1 mutation was present in two-thirds of the patients, of whom 41% were positive for a mutation causing haploinsufficiency, i.e. reduced fibrillin-1 protein, and 59% for a mutation leading to a dominant negative effect, i.e. abnormal fibrillin-1 protein. Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient mutation had a 2.5-fold higher risk for cardiovascular death, a 2.4-fold higher risk for death and dissection, and a 1.6-fold higher risk for any aortic complication compared with patients with a dominant negative mutation. The authors conclude that Marfan syndrome patients with a haploinsufficient mutation are at a markedly increased risk compared with those with a dominant negative mutation. The implications of these results are discussed in a thought-provoking Editorial by Bart L. Loeys from the Antwerp University Hospital in Belgium.19 Exercise intolerance is common in people with heart failure and preserved ejection fraction, so-called HFpEF.20 Right ventricular dysfunction has been shown at rest in HFpEF, but few data are available regarding dynamic right ventricular–pulmonary artery coupling during exercise. In their paper entitled ‘Abnormal right ventricular–pulmonary artery coupling with exercise in heart failure with preserved ejection fraction’, Barry A. Borlaug and colleagues from the Mayo Clinic in Rochester, Minnesota, USA studied this issue further.21 Fifty subjects with HFpEF and 24 healthy controls prospectively underwent invasive cardiopulmonary exercise testing using high fidelity micromanometer catheters along with simultaneous assessment of right ventricular and left ventricular mechanics by echocardiography. Compared with controls at rest, subjects with HFpEF displayed preserved right ventricular systolic and diastolic mechanics, i.e. right ventricular s' and e' impaired left ventricular s' and e', higher biventricular filling pressures, and higher pulmonary artery pressures. On exercise, subjects with HFpEF displayed less increase in stroke volume, heart rate, and cardiac output (CO), with blunted increase in CO relative to O2 consumption (VO2). Enhancement in right ventricular systolic and diastolic function on exercise was impaired in HFpEF compared with controls. Exercise-induced pulmonary artery vasodilation was also reduced in HFpEF and associated with greater pulmonary venous hypoxia. Elevations in biventricular filling pressures and limitations in CO reserve were strongly correlated with abnormal enhancement in ventricular mechanics in the right and left ventricule during stress. The authors conclude that in addition to limited left ventricular reserve, patients with HFpEF display impaired right ventricular reserve during exercise that is associated with high filling pressures and inadequate CO responses. These findings highlight the importance of biventricular dysfunction in HFpEF and suggest that novel therapies targeting myocardial reserve in both the right and left heart may be effective to improve symptoms. It is hoped that the readers of this issue of the European Heart Journal will find it of great interest.