Cardiovascular Pharmacogenetics: From Discovery of Genetic Association to Clinical Adoption of Derived Test.

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.

Comparison of the European and US guidelines for lipid-lowering therapy in primary prevention of cardiovascular disease.

AIMS: Population-wide impacts of new guidelines in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) should be explored in independent cohorts. Assess and compare the lipid-lowering therapy eligibility and predictive classification performance of 2016 and 2021 European Society of Cardiology (ESC), 2019 American Heart Association/American College of Cardiology (AHA/ACC), and 2022 US Preventive Services Task Force (USPSTF) guidelines. METHODS AND RESULTS: Participants from the CoLaus|PsyCoLaus study, without ASCVD and not taking lipid-lowering therapy at baseline. Derivation of 10-year risk for ASCVD using Systematic COronary Risk Evaluation (SCORE1), SCORE2 [including SCORE2-Older Persons (SCORE2-OP)], and pooled cohort equation. Computation of the number of people eligible for lipid-lowering therapy based on each guideline and assessment of discrimination and calibration metrics of the risk models using first incident ASCVD as an outcome. Among 4,092 individuals, 158 (3.9%) experienced an incident ASCVD during a median follow-up of 9 years (interquartile range, 1.1). Lipid-lowering therapy was recommended or considered in 40.2% (95% confidence interval, 38.2-42.2), 26.4% (24.6-28.2), 28.6% (26.7-30.5), and 22.6% (20.9-24.4) of women and in 62.1% (59.8-64.3), 58.7% (56.4-61.0), 52.6% (50.3-54.9), and 48.4% (46.1-50.7) of men according to the 2016 ESC, 2021 ESC, 2019 AHA/ACC, and 2022 USPSTF guidelines, respectively. 43.3 and 46.7% of women facing an incident ASCVD were not eligible for lipid-lowering therapy at baseline according to the 2021 ESC and 2022 USPSTF, compared with 21.7 and 38.3% using the 2016 ESC and 2019 AHA/ACC, respectively. CONCLUSION: Both the 2022 USPSTF and 2021 ESC guidelines particularly reduced lipid-lowering therapy eligibility in women. Nearly half of women who faced an incident ASCVD were not eligible for lipid-lowering therapy.

QUESTION: Compared with previous European and US guidelines, what are the population-wide impacts of the 2021 European Society of Cardiology (ESC) and 2022 US Preventive Services Task Force (USPSTF) guidelines for primary cardiovascular prevention in terms of lipid-lowering therapy eligibility and risk classification performance? KEY FINDINGS: In a population-based cohort study comprising 4069 adults free from cardiovascular disease and lipid-lowering treatment, the implementation of both guidelines resulted in a lower proportion of treatment-eligible individuals compared with the 2016 ESC and 2019 American Heart Association/American College of Cardiology guidelines, especially among women. In women, nearly half of 10-year incident cardiovascular events occurred in those for whom a lipid-lowering therapy was not recommended. Meanings: The 2021 ESC and 2022 USPSTF guidelines reduced overtreatment but did not improve the identification of individuals who will develop atherosclerotic cardiovascular disease. There is a need to better stratify the cardiovascular risk in women.

Complex Lemierre syndrome with multisystemic abscesses.

We present here the challenging case of severe Lemierre syndrome in a healthy woman in her late twenties, whose clinical presentation was characterised by lung abscesses and disseminated systemic abscesses in the brain, the abdomen and the soft-tissues, as a likely consequence of a patent foramen ovale. Blood cultures were positive for Fusobacterium necrophorum and a right lingual vein thrombosis was detected at a late stage when the patient developed a septic shock. Initial antimicrobial therapy with metronidazole and ceftriaxone was modified to meropenem due to progressive worsening. The patient underwent laparoscopy and neurosurgical drainage of a cerebral abscess. She spent many days in the intensive care unit and recovered fully after 6 weeks on meropenem therapy. Although considered rare, the incidence of Lemierre syndrome, a potentially life-threatening condition, is increasing. The clinician should promptly recognise and treat it while being aware of its potential atypical presentations.

Ten-Year Evolution of Statin Eligibility and Use in a Population-Based Cohort.

Studies showing that the management of dyslipidemia is suboptimal are hampered by their cross-sectional design or short follow-up. Using recent data from a population-based cohort with a 10-year follow-up, we assessed the use of statins, including their intensity. We used data from the CoLaus|PsyColaus study, involving 4,655 participants at baseline (2003 to 2006) and 3,587 at 10-year follow-up (2014 to 2017). We assessed the cardiovascular risk of participants according to established guidelines from the European Society of Cardiology (ESC) and from the American Heart Association/American College of Cardiology and estimated 10-year cardiovascular risk using corresponding risk scores, Systemic Coronary Risk Evaluation risk prediction model and Pooled Cohort Equations. We first determined eligibility for statins and adherence to recommendations at 2 time periods. Additionally, we assessed the prevalence of statin users from 2014 to 2017 in persons without atherosclerotic cardiovascular disease at baseline and who developed it during the follow-up (secondary prevention). A total of 219 participants developed a first atherosclerotic cardiovascular disease during follow-up. Statin use in eligible subjects was 25.9% and 24.0% from 2003 to 2006 and 35.9% and 26.3% from 2014 to 2017, according to ESC and American Heart Association/American College of Cardiology guidelines, respectively. Per ESC guidelines, only 28.2% of treated persons achieved low-density lipoproteins cholesterol target levels from 2014 to 2017 (15.8% from 2003 to 2006), and women less frequently attained goals. Only 18% of subjects used high-intensity statins from 2014 to 2017, with women less often receiving them (14% vs 22%). In secondary prevention, only 74% of eligible subjects were using statins. In conclusion, based on contemporaneous data, management of dyslipidemia is suboptimal, including in secondary prevention, especially in women who are less frequently treated and, if treated, less frequently receive high-intensity treatment.

Cardiovascular risk assessment in people living with HIV compared to the general population.

AIMS: We prospectively assessed and compared the accuracy of cardiovascular risk scores in people living with HIV (PLWH) and individuals from the general population. METHODS AND RESULTS: The Systematic Coronary Risk Evaluation Score 2 (SCORE2), the Pooled Cohort Equations (PCE), and the HIV-specific Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) score were calculated in participants free from atherosclerotic cardiovascular disease (ASCVD) between 2003 and 2009. In total, 6373 [mean age, 40.6 years (SD, 9.9)] PLWH from the Swiss HIV Cohort Study (SHCS) and 5403 [52.8 years (SD, 10.7)] individuals from the CoLaus|PsyCoLaus study were eligible for analysis. We tested discrimination and calibration, and the value of adding HIV-specific factors to scores using the net reclassification improvement (NRI). During mean follow-ups of 13.5 (SD, 4.1) in SHCS and 9.9 (SD, 2.3) years in CoLaus|PsyCoLaus study, 533 (8.4%) and 374 (6.9%) people developed an incident ASCVD, respectively. This translated into age-adjusted incidence rates of 12.9 and 7.5 per 1000 person-year, respectively. In SHCS, SCORE2, PCE, and D:A:D presented comparable discriminative capacities [area under the receiver operating characteristic curve of 0.745 (95% confidence interval, CI, 0.723-0.767), 0.757 (95% CI, 0.736-0.777), and 0.763 (95% CI, 0.743-0.783)]. Adding HIV-specific variables (CD4 nadir and abacavir exposure) to SCORE2 and PCE resulted in an NRI of -0.1% (95% CI, -1.24 to 1, P = 0.83) and of 2.7% (95% CI, 0.3-5.1, P = 0.03), respectively. CONCLUSIONS: PLWH present a two-fold higher rate of incident ASCVD compared to individuals from the general population. SCORE2 and PCE, which are clinically easier to use (reduced set of variables without adding HIV-specific factors), are valid to predict ASCVD in PLWH.