BackgroundIsolated systolic hypertension (ISH) of the young has been associated with both normal and increased cardiovascular risk, which has been attributed to differences in central systolic blood pressure and arterial stiffness.MethodsWe assessed the prevalence of ISH of the young and compared differences in central systolic blood pressure and arterial stiffness between ISH and other hypertensive phenotypes in a multi-ethnic population of 3744 subjects (44% men), aged <40 years, participating in the HELIUS study.ResultsThe overall prevalence of ISH was 2.7% (5.2% in men and 1.0% in women) with the highest prevalence in individuals of African descent. Subjects with ISH had lower central systolic blood pressure and pulse wave velocity compared with those with isolated diastolic or systolic-diastolic hypertension, resembling central systolic blood pressure and pulse wave velocity values observed in subjects with high-normal blood pressure. In addition, they had a lower augmentation index and larger stroke volume compared with all other hypertensive phenotypes. In subjects with ISH, increased systolic blood pressure amplification was associated with male gender, Dutch origin, lower age, taller stature, lower augmentation index and larger stroke volume.ConclusionISH of the young is a heterogeneous condition with average central systolic blood pressure values comparable to individuals with high-normal blood pressure. On an individual level ISH was associated with both normal and raised central systolic blood pressure. In subjects with ISH of the young, measurement of central systolic blood pressure may aid in discriminating high from low cardiovascular risk.

Microcirculatory EG dimension, as estimated by automated SDF imaging, is not associated with CVD, suggesting that this technique may not contribute to cardiovascular risk stratification.

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Adeno-associated virus serotype 8 (AAV8) has been demonstrated to be effective for liver-directed gene therapy in humans. Although hepatocytes are the main target cell for AAV8, there is a loss of the viral vector because of uptake by macrophages and Kupffer cells. Reducing this loss would increase the efficacy of viral gene therapy and allow a dose reduction. The receptor mediating this uptake has not been identified; a potential candidate seems the macrophage scavenger receptor A (SR-A) that is involved in the endocytosis of, for instance, adenovirus. In this study we show that SR-A can mediate scAAV8 endocytosis and that blocking it with polyinosinic acid (poly[i]) reduces endocytosis significantly in vitro. Subsequently, we demonstrate that blocking this receptor improves scAAV-mediated liver-directed gene therapy in a model for inherited hyperbilirubinemia, the uridine diphospho-glucuronyl transferase 1A1-deficient Gunn rat. In male rats, preadministration of poly[i] increases the efficacy of a low dose (1×10¹¹ gc/kg) but not of a higher dose (3×10¹¹ gc/kg) scAAV8-LP1-UT1A1. Administration of poly[i] just before the vector significantly increases the correction of serum bilirubin in female rats. In these, the effect of poly[i] is seen by both doses but is more pronounced in the females receiving the low vector, where it also results in a significant increase of bilirubin glucuronides in bile. In conclusion, this study shows that SR-A mediates the endocytosis of AAV8 in vitro and in vivo and that blocking this receptor can improve the efficacy of AAV-mediated liver-directed gene therapy.

BackgroundDifferences in arterial wave reflection and central blood pressure (BP) have been associated with cardiovascular disease (CVD) in various populations and may contribute to ethnic differences in CVD. Whether ethnic differences in wave reflection and central BP can be explained by conventional risk factors for CVD or may result from physiological differences remains undetermined.MethodsWe examined ethnic differences in augmentation index (AIx) and central systolic BP and their determinants in a large multi-ethnic cohort study in Amsterdam, the Netherlands. A total of 8812 (46% male) participants aged 18–70 years of Dutch, South-Asian Surinamese, African Surinamese and Ghanaian origin were included. AIx and central BP were measured in duplicate using the Arteriograph system.ResultsAIx and central systolic BP were significantly higher in South-Asian Surinamese (35±17%, 126±22 mmHg), African Surinamese (33±17%, 129±23 mmHg) and Ghanaian (33±16%, 135±24 mmHg) as compared with Dutch (27±17%, 118±20 mmHg, all p<0.001). Correction for cardiovascular risk factors only slightly reduced the difference in AIx, whereas correction for body height attenuated age and gender corrected ethnic differences in AIx the most. Differences in central systolic BP were primarily determined by differences in AIx for South-Asian Surinamese and by differences in peripheral systolic BP for subjects of African origin.ConclusionsSubstantial differences in AIx and central BP exist across different ethnic groups that cannot be explained by differences in conventional risk factors for CVD. These findings may explain part of the underestimation of cardiovascular risk observed in populations of African and South-Asian descent.