Serum free thyroxine levels are positively associated with arterial stiffness in the SardiNIA study.

OBJECTIVE: Thyroid dysfunction may accelerate atherosclerosis. Aortic pulse wave velocity (PWV) is an early index of arterial stiffness and an important risk factor for cardiovascular disease and might therefore be linked to changes in thyroid activity. We investigated the relationship between thyroid function and carotid-femoral PWV, as an index of arterial stiffness. DESIGN: Cross-sectional cohort study. PATIENTS: Participants from the SardiNIA study. Those being treated for thyroid diseases were excluded, yielding a sample of 5875 aged 14-102. MEASUREMENTS: Clinical parameters, blood tests including serum TSH and serum FT4, and carotid-femoral PWV were measured. RESULTS: After adjusting for confounders, a direct and linear association between FT4 and PWV was shown (multiple regression analysis). The model containing age, mean blood pressure, body mass index, heart rate, FT4, hypertension, diabetes and dyslipidaemia accounted for 55% of the variation in PWV. CONCLUSIONS: Like several other known risk factors, serum FT4 levels are associated with carotid-femoral PWV, suggesting that high FT4 levels have a detrimental effect on aortic stiffness and may contribute to ageing process of the vascular system. This finding may help to understand the pathogenesis of cardiovascular disease and contribute to improve prevention therapy.

HIV Infection Indicator Disease-Based Active Case Finding in a University Hospital: Results from the SHOT Project.

In 2014, UNAIDS launched renewed global targets for HIV control to achieve by 2025, known as "the three 95": 95% of people living with HIV (PWH) diagnosed, of which 95% are receiving treatment, of which 95% are on sustained virological suppression. In Italy, new HIV diagnoses have been steadily decreasing since 2012. However, in 2020, 41% of new diagnoses presented with less than 200 CD4+ cells/µL and 60% with less than 350 CD4+ cells/µL. Implementing testing and early treatment is a key strategy to prevent AIDS, late presentation, and HIV transmission. We selected non-Infectious Diseases Units based on the European project HIDES and engaged colleagues in a condition-guided HIV screening strategy. We enrolled 300 patients, of which 202 were males (67.3%) and 98 were females (32.7%). Most of the screening was performed in Infectious Diseases (ID) and Hematologic wards. In total, we diagnosed eleven new HIV infections with a hospital prevalence in the study population of 3.7%. Five (45.4%) had a CD4 count <100/mm3, one (9.1%) <200/mm3, and one (9.1%) <300/mm3. Regarding risk factors, 81.8% declared having had unprotected sexual intercourse and 54.5% were heterosexual. All patients promptly started a combination antiretroviral regimen and 10 (90.9%) obtained an undetectable HIV-RNA status. Eight of the eleven (72.7%) patients are currently on follow-up in our outpatient clinic. A proactive indicator disease-guided screening can help avoid missed opportunities to diagnose HIV infection in a hospital setting. Implementing this kind of intervention could favor early diagnosis and access to treatment.

Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.

Essential hypertension remains a major risk factor for cardiovascular and cerebrovascular diseases. As a complex multifactorial disease, elucidation of susceptibility loci remains elusive. ATP1A1 and Dear are candidate genes for 2 closely linked rat chromosome-2 blood pressure quantitative trait loci. Because corresponding human syntenic regions are on different chromosomes, investigation of ATP1A1 (chromosome [chr]-1p21) and Dear (chr-4q31.3) facilitates genetic analyses of each blood pressure quantitative trait locus in human hypertension. Here we report the association of human ATP1A1 (P<0.000005) and Dear (P<0.03) with hypertension in a relatively isolated, case/control hypertension cohort from northern Sardinia by single-nucleotide polymorphism haplotype analysis. Sex-specific haplotype analyses detected stronger association of both loci with hypertension in males than in females. Haplotype trend-regression analyses support ATP1A1 and Dear as independent susceptibility loci and reveal haplotype-specific association with hypertension and normotension, thus delineating haplotype-specific subsets of hypertension. Although investigation in other cohorts needs to be performed to determine genetic effects in other populations, haplotype subtyping already allows systematic stratification of susceptibility and, hence, clinical heterogeneity, a prerequisite for unraveling the polygenic etiology and polygene-environment interactions in essential hypertension. As hypertension susceptibility genes, coexpression of ATP1A1 and Dear in both renal tubular cells and vascular endothelium suggest a cellular pathogenic scaffold for polygenic mechanisms of hypertension, as well as the hypothesis that ATP1A1 and/or Dear could contribute to the known renal and vascular endothelial dysfunction associated with essential (polygenic) hypertension.

Genetic polymorphism of the renin-angiotensin-aldosterone system and arterial hypertension in the Italian population: the GENIPER Project.

OBJECTIVE: To detect the association of single polymorphisms of the renin-angiotensin-aldosterone system (RAAS), or different combinations thereof, with hypertension. DESIGN AND METHODS: The GENIPER database is the result of a collaborative effort of 13 Italian research centres to collect genomic DNA in subjects well characterized in terms of blood pressure status. A total of 2461 subjects (normotensive = 611; hypertensive = 1850) were selected and genotyped for the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) T/C704, angiotensin receptor type 1 (AT1) A/C1166 and aldosterone synthase (ALDO) T/C-344 genetic variants. RESULTS: Allele frequencies were homogeneous over the Italian territory, with the relevant exception of the ACE I/D, the D allele being significantly less frequent in the northern region (61%) than in the rest of the country (67%; P < 0.0001). When comparing allele and genotype distributions in normotensives and hypertensives, the latter presented a small but statistically significant increase of the C allele of AGT T/C704, the A allele of AT1 A/C1166 and the T allele of ALDO T/C-344 polymorphisms (P = 0.018, P = 0.037 and P = 0.015, respectively), with similar trends all over the country. A step-wise logistic regression analysis confirmed these findings, by entering in the model as independent predictors of blood pressure status of AGT T/C704 (P = 0.013), ALDO T/C-344 (P = 0.032) and AT1 A/C1166 polymorphisms (P = 0.075), but not ACE I/D (P = 0.996). We also found some evidence of an additive effect of individual genetic variants of the RAAS, modulating at different levels the same functional pathway, on the risk of developing hypertension, but no synergistic interaction was observed. CONCLUSIONS: Our results suggest that some allelic variants of RAAS genes carry a small but identifiable risk of developing arterial hypertension.

Genetic prediction of heart failure incidence, prognosis and beta-blocker response.

Heart failure (HF) is a widespread syndrome due to left ventricular dysfunction with high mortality, morbidity and health-care costs. Beta-blockers, together with diuretics and ACE-inhibitors or angiotensin receptor blockers, are a cornerstone of HF therapy, as they reduce mortality and morbidity. Nevertheless, their efficacy varies among patients, and genetics is likely to be one of the modifying factors. In this article, literature on the role of candidate genes on the development of HF, its prognosis and pharmacogenomics of ß-blockers in patients with HF is reviewed. The available findings do not support, at the present time, a role for genetic tests in the treatment of HF. More large-scale genome-wide studies with adequate methodology and statistical analysis are required before considering genetic tailoring of HF therapy in patients with systolic HF.

Haplotypes of the adrenergic system predict the blood pressure response to beta-blockers in women with essential hypertension.

AIMS: To analyze the association of haplotypes of the adrenergic system with essential hypertension and with the blood pressure response to beta-blockers. MATERIALS & METHODS: In 1112 never-treated essential hypertension patients and 203 normotensive controls, tightly linked SNPs of beta-adrenergic receptors (ADRB1 - Ser49Gly and Arg389Gly; ADRB2 - Cys19Arg, Gly16Arg and Gln27Glu) and the G-protein beta3-subunit (GNB3 - A3882C, G5249A and C825T) were genotyped. Association of haplotypes with essential hypertension and with the blood pressure response to atenolol 50 mg twice daily in a subgroup of essential hypertension patients (n = 340) was evaluated (Haploview 3.2). RESULTS: No SNPs or haplotypes were associated with essential hypertension. In females only, GNB3 SNPs and haplotypes were associated with the blood pressure response (p < 0.05). CONCLUSION: Our study confirmed the sex-specific association of GNB3 with the blood pressure response to atenolol with no substantial advantage of the analysis of haplotypes over SNPs.

Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia.

OBJECTIVE: Autosomal recessive hypercholesterolemia (ARH) is a lipid disorder caused by mutations in a specific adaptor protein for the LDL receptor. ARH is rare except in Sardinia where three alleles (ARH1, ARH2 and ARH3) explain most of cases. The prevalence of ARH heterozygotes in Sardinia is not well determined as well as inconclusive data are available on the effect of the ARH carrier status on LDL cholesterol (LDL-C) and coronary risk. METHODS: 3410 Sardinians (986 blood donors, 1709 with hypertension and 715 with myocardial infarction (MI)) were screened for ARH alleles. For comparison purposes, lipid data of 60 ARH heterozygous carriers and 60 non-carriers identified within 24 ARH families were also considered. RESULTS: In the whole study cohort, no ARH homozygotes were found, but 15 ARH1 (0.44%) and 9 ARH2 (0.26%) heterozygous carriers were identified. The frequency of ARH alleles in blood donors was 0.0030, not different from that in hypertensive subjects (0.0032). ARH alleles tended to be more common in MI patients (0.0049), but no association between ARH carrier status and MI risk was detected after controlling for conventional risk factors. ARH carriers and non-carriers showed similar LDL-C levels. This result was confirmed when ARH carriers and non-carriers identified throughout family-based and population-based screenings were combined and compared (141.0+/-41 mg/dl vs. 137.0+/-41 mg/dl, respectively; p=0.19). CONCLUSIONS: These data indicate that the frequency of ARH heterozygotes in Sardinia is approximately 1:143 individuals, thus making this condition one of the most common in the Sardinian population. However, ARH carrier status does not influence LDL-C concentration and coronary risk, thus suggesting that ARH can be regarded as a truly recessive disorder.

Clinical variables, not RAAS polymorphisms, predict blood pressure response to ACE inhibitors in Sardinians.

AIM: No definite factors predict blood pressure response to angiotensin-converting enzyme-inhibitors. The aim of this study was to test the association of gene polymorphisms of the renin-angiotensin-aldosterone system with essential hypertension and anthropometric variables, intermediate phenotypes and gene polymorphisms with blood pressure after fosinopril in a genetically homogeneous cohort. METHODS: A total of 630 essential hypertension patients, not previously treated or out of antihypertensive treatment for at least 6 months versus 219 normotensives (genotype frequencies, chi(2)). A total of 191 patients were randomly assigned to fosinopril 20 mg/day. Samples for plasma renin activity and aldosterone, 24-h urinary sodium (flame photometry) were collected. Gene polymorphisms--angiotensin-converting enzyme (insertion/deletion), angiotensin II type 1-receptor (A1166C), aldosterone synthase (-344C/T) and angiotensinogen (-6A/G)--were analyzed by standard techniques. The association of anthropometric variables, intermediate phenotypes and gene polymorphisms with blood pressure after 4 weeks therapy was tested by univariate analysis and analysis of covariance model (Intercooled Stata SE 9.2). RESULTS: No genetic polymorphisms were associated with essential hypertension, blood pressure response and intermediate phenotypes (p > 0.05). Systolic blood pressure after therapy was associated with baseline systolic blood pressure, age and sex. CONCLUSIONS: Our results confirm the difficulty in dissecting both essential hypertension and pharmacogenomics when analyzing the effect of single genes in complex multifactorial traits.

11beta-Hydroxysteroid dehydrogenase type 2 activity is associated with left ventricular mass in essential hypertension.

AIMS: Left ventricular mass (LVM) is under the control of aldosterone and angiotensin II in experimental hypertension, but the effect of aldosterone on LVM is controversial in essential hypertension (EH). Some EH patients show a mild impairment of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity without clinical features of the syndrome of apparent mineralocorticoid excess, where the incomplete cortisol-to-cortisone conversion leads to glucocorticoid-mediated mineralocorticoid effects. The mineralocorticoid receptor and 11beta-HSD2 are co-expressed in human heart. We investigated whether LVM may be regulated by glucocorticoids in EH patients. METHODS AND RESULTS: The ratio between 24 h urinary tetrahydro derivatives of cortisol and cortisone (THFs/THE), plasma renin activity, 24 h urinary aldosterone, blood pressure, and LVM indexed for height(2.7) (LVMh(2.7)) were analysed in 493 never-treated hypertensives and 98 normotensives. THFs/THE was associated with LVMh(2.7) in hypertensives and normotensives (r=0.32, P<0.001, and r=0.17, P=0.04, respectively) and persisted after adjusting for confounders (multiple regression analysis). Body mass index, sex, recumbent plasma renin activity, and THFs/THE accounted for 26.1% of LVMh(2.7) variation. Urinary aldosterone was not correlated with LVMh(2.7). CONCLUSION: We suggest that glucocorticoids may take part in the regulation of LVM in EH patients as a function of 11beta-HSD2 activity, and contribute to the target organ damage associated with essential hypertension.

Role of HSD11B2 polymorphisms in essential hypertension and the diuretic response to thiazides.

BACKGROUND: The renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thereby protecting the nonselective mineralocorticoid (MR) receptor from occupation by glucocorticoids. Loss-of-function mutations in the gene encoding 11beta HSD2 (HSD11B2) result in overstimulation of the MR and cause salt-sensitive hypertension. METHODS: We have investigated the role of HSD11B2 in hypertension in 377 genetically homogeneous essential hypertensives from North Sardinia. RESULTS: Thirty of these patients displayed increased urinary cortisol metabolite ratios (greater than or equal to 2) (tetrahydrocortisol [THF]+allotetrahydrocortisol [aTHF]/tetrahydrocortisone [THE]) reflecting a mild reduction in 11beta HSD2 activity. No mutations in HSD11B2 were detected in these patients. All 377 patients were genotyped for a CA repeat microsatellite in intron 1 of HSD11B2 and a G534A polymorphism in exon 3 of HSD11B2. CA repeat length was associated with the (THF+aTHF)/THE ratio, which in turn was significantly related to PRA levels. No associations were found between the G354A polymorphism and the other parameters. There were no differences in blood pressure (BP) levels between HSD11B2 genotypes, but in a subgroup of 91 patients that underwent diuretic therapy, CA repeat length was strongly associated with the BP response to hydrochlorothiazide. CONCLUSION: This study highlights the role of this HSD11B2 polymorphism in sodium handling and is consistent with a role in the BP response to thiazide diuretics.

alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives.

Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if alpha-adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P<0.0001), whereas intracellular Na concentration was lower (P<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp alpha-adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp alpha-adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients.