Stefano Taddei

Accelerated atherosclerosis is one of the major causes of morbidity in patients with systemic lupus erythematosus (SLE). Endothelial dysfunction (ED) is considered an early marker of atherosclerosis. It is a reversible alteration, thus representing an attractive target for prevention strategies against cardiovascular disease. Studies have shown that ED occurs in patients with SLE even in the absence of severe, active disease. Hydroxychloroquine (HCQ) is widely used in SLE to control disease activity, but its use is also associated with an improvement in long-term prognosis. Beyond the beneficial effect in well-established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE. The aim of this study was to assess the impact of early treatment with HCQ on ED in a murine model of SLE. Twelve-week-old NZB/W F1 (NZ) and C57BL/6 J mice (controls) were allocated to receive HCQ or vehicle for 6, 12, or 18 weeks. Proteinuria and anti–double-stranded DNA autoantibodies were determined. ED was assessed in mesenteric arteries (pressurized myography). Nitric oxide (NO) availability and reactive oxygen species (ROS) production were evaluated. Vascular ROS production was measured with dihydroethidium (DHE) fluorescent dye. Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals. HCQ administration normalized the NO availability in the up to 24-week-old group, with a partial amelioration in the 30-week-old group. DHE analysis revealed a progressive increment of vascular ROS generation among NZ groups, which was prevented by apocynin. Similarly, in the NZ HCQ-treated group, vascular ROS production was abrogated. The ED that characterizes this mouse model of SLE is caused by the nicotinamide adenine dinucleotide phosphate oxidase–driven ROS excess. Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect.

Endothelial dysfunction and arterial stiffness are early vascular alterations, linked to oxidative stress and inflammation, with prognostic significance in essential hypertensive patients. P2X7 receptors (P2X7R), responding to extracellular ATP, are encoded by a highly polymorphic gene and modulate inflammatory responses and cell growth, potentially playing a role in the control of vascular tone. This study evaluated the effects of P2X7R gene polymorphisms (single nucleotide polymorphisms, SNPs) on a detailed vascular hypertensive phenotype. We determined by real-time PCR two SNPs of the P2X7R gene (489C>T and 1513A>C) in 134 newly diagnosed, treatment-naive essential hypertensive patients and 131 normotensive controls (CTL). Endothelium-dependent response was assessed as flow-mediated dilatation (FMD) of the brachial artery, arterial stiffness as aortic pulse wave velocity (PWV) and augmentation index (AIx) by tonometry. Markers of oxidative stress were also measured. FMD was lower (P < 0.05), whereas aortic PWV and AIx were higher (P < 0.01) in essential hypertensive patients than in CTL. The allelic distribution of the two P2X7R SNPs was similar in essential hypertensive patients and CTL, either concerning homozygosis or presence of the mutant alleles. No difference was observed for FMD, aortic PWV, AIx or markers of oxidative stress between carriers and noncarriers of the mutant alleles, either in essential hypertensive patients and in CTL. In the whole group, logistic regression showed that the mutant allele of 1513A>C was a main determinant of AIx (odds ratio 1.90; P = 0.03). P2X7R 489C>T and 1513A>C SNPs are not associated with altered endothelial function or arterial stiffness in untreated newly diagnosed essential hypertensive patients; a possible role in influencing peripheral wave reflection should be further addressed.

Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient’s therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated.

Control of cardiovascular (CV) risk factors, particularly hypertension, is still unsatisfactory, resulting in excess CV morbidity and mortality worldwide. CV risk is linearly associated with an increase in blood pressure (BP) values, and clinical studies have clearly demonstrated that BP lowering represents the most effective means of preventing CV events. However, while BP reduction is a fairly easy target, BP normalization is much more difficult to achieve, and adequate BP control (<140/90 mmHg) is attained only in a small percentage of the hypertensive population.

It is widely recognized that around 20% of cardiovascular events occurring in the general population cannot be inferred from conventional risk factors.¹ This led to a growing interest in novel measurable humoral biomarkers, hopefully leading to an improvement of global cardiovascular risk stratification. Growth differentiation factor-15 (GDF-15) is the latest promising marker in this field. Growth differentiation factor-15 is a protein belonging to the transforming growth factor-β (TGF-β) superfamily, which includes more than 40 proteins with crucial functions in adult tissue homeostasis by modulating cell survival, proliferation, differentiation, and tissue repair in different organs. Initially cloned from an activated macrophage cell line, GDF-15 has been proposed as a cell death promoter in several tumour cell lines, highlighting its potential role as an inductor of apoptosis in some cancer cells.² Expression of GDF-15 is rapidly induced by IL-1, TNF-α, and TGF-β in macrophages, thereby limiting macrophage activation and inflammation.³ Results of analysis from human tissues evidenced the presence of GDF-15 also in the kidney, prostate and placenta, breast and colon, as well as in the heart.³

Phosphodiesterase (PDE) 5 inhibitors reduce cyclic guanylate monophosphate breakdown, promoting vascular relaxation in the corpora cavernosa and penile erection during sexual stimulation. Sildenafil, vardenafil, and tadalafil were approved as effective treatments for male erectile dysfunction. Because PDE5 is present in artery and vein smooth muscle cells throughout the body, PDE5 inhibitors have mild systemic vasodilatory effects and thus the potential to impact the vascular system. The US Food and Drug Administration has approved PDE5 inhibitors for treating pulmonary hypertension. Moreover, their systemic vasodilating properties theoretically make these drugs suitable for treating hypertension. Studies indicate that PDE5 inhibition may be an option for reducing blood pressure in hypertensive patients. Additional benefits may be related to improved arterial stiffness and endothelial dysfunction, two early vascular abnormalities characterizing essential hypertension. More investigation is needed on PDE5 inhibitors as antihypertensive drugs, especially with slow-release formulations or compounds with long half-life. Studies on safety during long-term administration, interactions with antihypertensive and nonantihypertensive drugs, and effect on target organ damage are needed.