Titolo della tesi: CARDIOVASCULAR RISK ASSESSMENT AND DIAGNOSTIC WORK-UP IN RARE DISEASES: FOCUS ON HYPERALDOSTERONISM AND PRIMARY ANTIBODY DEFICIENCY
Introduction: Unilateral form of primary aldosteronism (PA) is the main curable cause of endocrine hypertension cause of PA and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of unilateral PA. The in vitro evidences of macrolide antibiotics specifically inhibit the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of unilateral PA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated unilateral PA.
Aim: To test the effect of roxithromycin on aldosterone secretion and blood pressure in vivo in patients without PA, and in those with PA subtyped by AVS and examined according to the presence or absence of KCNJ5 mutation.
Methods: We enrolled consecutive hypertensive patients undergoing screening for secondary hypertension, from January 2018 to June 2022. Each patient received a single oral dose of roxithromycin and, after the diagnostic work-up, baseline values of plasma aldosterone concentration (PAC) and blood pressure were compared with post-roxithromycin values. Next- generation sequencing (NGS) was used to identify KCNJ5 mutated from wild-type forms of unilateral PA. Response to roxithromycin was compared between non-PA, non-unilateral PA and unilateral PA. In unilateral PA we focused on KCNJ5 mutated vs wild-type patients.
Results: After roxithromycin administration, patients with unilateral PA carring KCNJ5 mutation showed a decrease in PAC (p=0.030) that did not occur in unilateral PA KCNJ5 wild-type. In these groups systolic blood pressure (SBP) and diastolic blood pressure (DBP) did not change in response to roxithromycin. However, in non-PA group a decrease in PAC was observed (p<0.001) with a decrease in plasma cortisol concentration (PCC) (p<0.001) and systolic (p<0.001) but not diastolic blood pressure. After adrenalectomy, roxithromycin did not induce any change in PAC in KCNJ5 mutated unilateral PA.
Conclusion: Roxithromycin administration induces a decrease in aldosterone production in patients with KCNJ5 mutation but not in wild-type, confirming its ability in vivo to blunt aldosterone production by blocking the mutated Kir3.4 sodium channel without affecting wild-type forms. As the decrease in PAC in the same patients did not occur after adrenalectomy, the roxithromycin effect is unequivocally attributable to the KCNJ5 mutated unilateral PA.
Introduction: Although the immune system is involved in vascular disorders, the actual role of B cells in atherosclerotic cardiovascular disease (ASCVD) remains unclear. Inflammatory conditions like Rheumatoid Arthritis and Systemic Lupus Erythematosus present an accelerated atherosclerotic process, that is somehow limited by appropriate treatment, including B cell depleting therapies. Common Variable Immunodeficiency (CVID) is a rare primary immunodeficiency of adulthood and represents a pathological condition suitable for studying the role of B cells in ASCVD. The cardiovascular risk profile of patients affected by this rare disease is unexplored and it is unclear whether CVID patients are protected towards atherogenesis.
Aim: We investigated the prevalence of cardiovascular risk factors and the presence of subclinical ASCVD in CVID patients.
Methods: We collected anamnestic clinical and biochemical data related to CVID and to ASCVD in a single center cohort of CVID patients, grouped according to clinical and immunological phenotype. At follow-up visit vascular structural and functional investigation was performed by SphygmoCor(R) XCEL instrument while droplet digital PCR analysis was used to assess gene expression.
Results: 127 CVID patients were enrolled in the study. Patients with complicated phenotype presented significantly lower levels of cholesterol and blood glucose, despite a significantly higher use of corticosteroids (p=0.014) due to higher frequency of GLILD (p<0.001) and autoimmunity(p=0.007), particularly ITP (p<0.001). Patients with Chapel phenotype 2 and 3 presented the lowest cholesterol and HbA1c levels. No significant difference was found in terms of metabolic syndrome, hypertension, diabetes, anti-hypertensive, anti diabetic and lipid lowering ongoing treatment, as well as acute cardiovascular events between complicated and uncomplicated phenotype. Lower IgA, IgM IgG levels at diagnosis, SmB cells % as well as higher T-LGL % (CD3+CD8+CD57+) and monthly dosage of IgRT in the complicated group were the main between groups significantly different immunologic parameters. In vivo measurement by SphygmoCor(R) XCEL instrument in a subgroup of 55 patients showed significant difference pulse pressure and augmentation pressure, with a tendence towards higher arterial thickness in patients with only infections. In the same subgroup, B lymphocytes isolated from pheripheral blood of patients with complicated phenotype presented a borderline-significantly higher expression of LDL receptor gene at droplet digital PCR analysis (p=0.053). Conclusion: Our data suggest that clinical phenotypes of CVID may be associated with different cardiovascular risk profiles, possibly based on the different underlying immunological alterations. Preliminary data suggests that B cell defects in CVID patients might influence the development of cardiovascular disease leading to different cardiovascular risk profile. The role of IgRT also needs to be explored. Follow-up studies will unravel the significance of our subclinical findings in terms of development of overt disease, with possible implications in terms of new therapeutic strategies for ASCVD.