Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study.

BACKGROUND AND AIMS: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. METHODS: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. RESULTS: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. CONCLUSIONS: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Decreased nighttime heart rate variability is associated with increased stroke risk.

BACKGROUND AND PURPOSE: Prediction of stroke in healthy individuals is challenging and there is a diurnal variation of stroke onset. We hypothesized that heart rate variability with a focus on nighttime heart rate variability will predict the risk of stroke in apparently healthy middle-age and elderly subjects. METHODS: The population-based cohort of the Copenhagen Holter Study, consisting of 678 healthy subjects between age 55 and 75 years with no history of cardiovascular disease or stroke, was evaluated. All underwent 48-hour ambulatory electrocardiogram monitoring. The SD of normal-to-normal RR intervals (SDNN) was selected as the method of measuring heart rate variability. Nighttime SDNN was measured between 02:00 and 02:15 AM and could be evaluated in 653 subjects. Median follow-up was 76 months. RESULTS: Nighttime SDNN was lower in women than in men (P=0.0008), and in diabetics than nondiabetics (P=0.03). However, smoking, cholesterol, systolic blood pressure, and age were not associated with nighttime SDNN. The risk of stroke was significantly associated with nighttime SDNN in a univariate analysis (HR, 0.66; 95% CI, 0.50-0.88; P=0.004) and after adjustment for conventional risk factors (HR, 0.67; 95% CI, 0.51-0.89; P=0.005) per 10 ms increments of SDNN. Eighty-one percent of all strokes (21/26) occurred in 330 subjects with the lower half of nighttime SDNN (≤38 ms; HR, 4.31; 95% CI, 1.62-11.42; P=0.003). CONCLUSIONS: Nocturnal heart rate variability is a strong marker for the development of stroke in apparently healthy subjects. The mechanism is unknown, but reduced parasympathetic activity may increase the risk of stroke by increasing the risk of arrhythmias.

Mild hyponatremia carries a poor prognosis in community subjects.

OBJECTIVE: Hyponatremia has been shown to predict adverse outcome in congestive heart failure and pneumonia among other common clinical entities, but its significance in the general population is elusive. METHODS: The population-based Copenhagen Holter Study included 671 men and women aged 55 to 75 years with no history of cardiovascular disease, stroke, or cancer. Baseline evaluation included 48-hour ambulatory electrocardiogram monitoring, blood tests, and a questionnaire. Hyponatremia was defined as s-Na < or = 134 mEq/L or s-Na < or = 137 mEq/L according to previously accepted definitions. An adverse outcome was defined as deaths or myocardial infarction. Median follow-up was 6.3 years. RESULTS: Fourteen subjects (2.1%, group A) had s-Na < or = 134 mEq/L, and 62 subjects (9.2%, group B) had s-Na < or = 137 mEq/L. No subject had s-Na < 129 mEq/L. An adverse outcome occurred in 43% of group A, 27% of group B, and 14% of subjects with s-Na >137 mEq/L (controls) (P < .002). Adjusted hazard ratio for adverse outcome was 3.56 (95% confidence interval [CI], 1.53-8.28, P < .005) in group A compared with controls and 2.21 (95% CI, 1.29-3.80, P < .005) in group B after controlling for age, gender, smoking, diabetes, low-density lipoprotein cholesterol, and blood pressure. The hazard ratios were robust for additional adjusting for variables showing univariate association to hyponatremia (ie, beta-blocker and diuretic use, heart rate variability, creatinine, C-reactive protein, and NT-pro brain natriuretic peptide). By excluding diuretic users (18% of subjects), the adjusted hazard ratio for adverse outcome was 8.00 (95% CI, 3.04-21.0, P < .0001) in group A and 3.17 (95% CI, 1.76-5.72, P = .0001) in group B compared with controls. CONCLUSION: Hyponatremia is an independent predictor of deaths and myocardial infarction in middle-aged and elderly community subjects.