Current Vascular Pharmacology - Volume 16, Issue 2, 2018

Background: The optimal antithrombotic therapies for transcatheter aortic valve implantation (TAVI) and MitraClip implantation have not been well established. We conducted a narrative review from currently available studies between January 2002 and May 2016 to highlight the advantages and disadvantages of antithrombotic therapy use in cardiac catheter-based therapeutic techniques. Recently, these techniques have dramatically altered the approach towards valvular heart diseases management. The introduction into clinical practice, of TAVI for severe aortic stenosis and MitraClip for mitral regurgitation, has revolutionized interventional cardiology. However, TAVI is associated with a risk of cerebral embolization and ischaemic vascular events leading to neurological impairment and even death. These ischaemic complications might occur perioperatively or much later, although the estimated rate of occurrence is variable. Conclusion: We will discuss prior experience with MitraClip for antithrombotic use. It is imperative for patients undergoing transcatheter valvular interventions to have optimal antithrombotic therapy that balances between ischaemic and haemorrhagic complications. The appropriate timing, combination, and duration of antithrombotic medications need consensus to weigh between the efficacy, efficiency and adverse effects in patients with transcatheter valvular interventions.

Background: Abdominal aortic aneurysm (AAA), a progressive segmental abdominal aortic dilation, is associated with high mortality. AAA is characterized by inflammation, smooth muscle cell (SMC) depletion and extracellular matrix (ECM) degradation. Surgical intervention and endovascular therapy are recommended to prevent rupture of large AAAs. Unfortunately, there is no reliable pharmacological agent available to limit AAA expansion. In the past decades, extensive investigations and a body of ongoing clinical trials aimed at defining potent treatments to inhibit and even regress AAA growth. Conclusion: In this review, we summarized recent progress of potential strategies, particularly macrolides, tetracyclines, statins, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, corticosteroid, anti-platelet drugs and mast cell stabilizers. We also consider recently identified novel molecular targets, which have potential to be translated into clinical practice in the future.

Background: Atherosclerosis is a systemic disease with different faces. Despite similar, or even identical, risk factors and pathogenesis, atherosclerotic lesions and their clinical manifestations vary in different parts of the vasculature. Peripheral arterial disease (PAD) in the superficial femoral artery (SFA) represents a frequent clinical manifestation of atherosclerotic disease. The pathohistological characteristics of plaques in PAD differ from lesions in the coronary arteries. Plaques in the SFA have more fibrotic elements with less lipid and degenerative tissue elements; this makes them more stable and less prone to rupture. The density of vasa vasorum, an important determinant of structure and stability of atherosclerotic lesions, is significantly lower in PAD than in coronary arteries. Further, haemodynamic forces and shear stress vary in different segments of the arterial tree and influence the development of atherosclerotic lesions and their stability. It follows that the clinical consequences differ depending on the vascular territory involved. In the coronary arteries, acute thrombotic occlusion with clinical manifestation of myocardial infarction is one of the most frequent manifestations due to unstable atherosclerotic lesions. Atherosclerotic lesions in SFA progress slowly and are more stable; therefore, clinical manifestations develop more gradually. Conclusion: The atherosclerotic process in SFA is frequently asymptomatic or presents as stable intermittent claudication, and in a relatively low percentage, progresses to critical limb ischaemia. Also, remodelling of the arterial wall in peripheral arteries compensates for the reduction of arterial lumen and provides blood flow in spite of relatively large atherosclerotic lesions. However, arterial restenosis after recanalization procedures in SFA reduces the long-term success of recanalization.

Background: Sexual dysfunction affects millions of people with an increasing prevalence, worldwide. The pathophysiology of the disease shares several similarities with cardiovascular disease (CVD), including atherosclerosis, endothelial dysfunction, structural vascular damage and subclinical inflammation. Erectile dysfunction (ED) and female sexual dysfunction are common among patients with CVD and risk factors such as hypertension, diabetes, obesity and metabolic syndrome. Given the common pathogenesis of the diseases, ED is an independent prognostic factor of future ED events. Patients with overt ED or risk factors are usually treated with several drugs for the management of these conditions. Several of these drugs have been evaluated for their effect on sexual activity. Results and Conclusion: Among the antihypertensive drugs, diuretics and beta-blockers seem to exert a detrimental impact on sexual function, with nebivolol being the only beta-blocker with favorable properties through an increase in nitric oxide bioavailability. In contrast, renin-angiotensin system inhibitors and calcium-channel blockers have a neutral effect on sexual activity. Hypoglycemic drugs have been less evaluated in the ED setting, with metformin, pioglitazone and liraglutide presenting favorable results. Statins on the other hand have not provided consistent results with observational studies suggesting a detrimental role in sexual activity and a few randomized studies indicating a neutral or even beneficial effect on erectile function.

Background: Patients affected by Chronic Kidney Disease and Mineral Bone Disorder (CKD-MBD) have a high risk of cardiovascular (CV) mortality that is poorly explained by traditional risk factors. The newest medical treatments for CKD-MBD have been associated with encouraging, but still inconsistent, improvement in CV disease complications and patient survival. A better understanding of the biomarkers and mechanisms of left ventricular hypertrophy (LVH), atherosclerosis, and vascular calcification (VC) may help with diagnosis and treatment of the organ damage that occurs secondary to CKD-MBD, thus improving survival. Recent insights about fibroblast growth factor-23 (FGF23) and its co-receptor, Klotho, have led to marked advancement in interpreting data on vascular aging and CKDMBD. Conclusion: This review will discuss the current experimental and clinical evidence regarding FGF23 and Klotho, with a particular focus on their roles in LVH, atherosclerosis, and VC.

Even mild abnormalities of the renal structure or function can increase the risk of mortality and complications in other organs. Therefore, safe and effective treatments are necessary in order to influence the progression of renal disease. We used 2 methods to assess the renoprotective effects of aliskiren: 1) a statistical analysis of clinical trials that investigated aliskiren-induced renoprotection, in terms of changes in serum creatinine concentration (sCr) or estimated glomerular filtration rate (eGFR), and, 2) clinical trials that investigated the renoprotective effects of aliskiren with respect to changes in albuminuria or proteinuria. In the forest plot, the overall risk ratio (%) for renal impairment with respect to changes in sCr or eGFR was 0.97 (0.88-1.06; overall p=0.48). The tabulation of data from clinical trials included 10 entries for monotherapy with aliskiren and 6 entries for add-on aliskiren. All of the clinical trials, except one, showed a decrease in proteinuria or albuminuria following aliskiren treatment. In conclusion, inhibiting renin and prorenin with aliskiren is a more promising renoprotective treatment compared with blocking the renin/prorenin receptors (RPR). One of the main mechanisms by which aliskiren may confer renoprotection is by decreasing albuminuria and proteinuria. However, it does not seem to change sCr and eGFR in patients at risk of developing renal disease. Furthermore, co-administration of an angiotensinconverting- enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) and aliskiren was shown to decrease albuminuria and proteinuria to a greater extent compared with monotherapy with these agents.

Background: Abdominal aortic aneurysm (AAA) formation is associated with by inflammation and matrix degradation. This study tested the hypothesis that calprotectin, a novel biomarker for inflammation, as well as established biomarkers such as C-reactive protein (CRP) and matrix metalloproteinase- 9 (MMP-9) could also be indicative inflammatory biomarkers during AAA pathogenesis and progression. We also evaluated the correlation of serum soluble Receptor for Advanced Glycation End Products (sRAGE) with AAA diameter and serum calprotectin levels. Materials and Methods: Rat abdominal aortas were perfused with porcine pancreatic elastase (AAA Group) or saline (Control Group) and studied on post-perfusion days 7 and 14 (n=11 per treatment group). Aneurysm was defined as a dilatation of the aorta above 150% of its original diameter. Laparotomy was performed on days 0 (T0), 7 (T7) and 14 (T14) for aortic diameter measurement. At the same time intervals, we measured the serum levels of calprotectin, CRP, sRAGE and MMP-9. Results: All animals developed AAA and no rupture occurred. MMP-9 in AAA group at T14 (p<0.05 compared with T7 and p<0.005 compared with T0) and calprotectin in AAA group at T14 (p<0.001 compared with T7 and T0) continued to significantly increase at all times. Serum sRAGE was significantly lower in the AAA group compared with the control group and within AAA group at all time points (p<0.001). On the other hand, the highest levels of CRP were identified at T7 in both groups. Calprotectin concentrations in AAA group were significantly higher compared with controls at T7 and T14 (p<0.001 and p<0.001, respectively). Aortic diameter was significantly correlated with MMP-9 and calprotectin serum concentrations at all time points (r=0.51, p<0.001; r=0.728, p<0.001 respectively). Serum sRAGE levels were significantly correlated with aortic diameter at all time points (r=-0.48, p<0.001) and serum calprotectin levels (r=-0.22, p<0.001). Conclusion: This is the first evaluation of calprotectin as an AAA inflammation biomarker. It seems to be a promising marker related to AAA natural history. Further experimental and large human studies are needed to fully elucidate the role of calprotectin in the development and progression of AAAs.

Background: Catheter-directed Ultrasound-Assisted Thrombolysis (USAT) is a novel technology providing a high efficacy with a reduced bleeding risk in patients with pulmonary embolism (PE). Methods: We performed a meta-analysis based on presented or published PE series in which USAT was utilized. We searched the MEDLINE, EMBASE and the Cochrane Library for trials published up to December 2015. Results: The primary outcomes were mean pulmonary artery pressure (PAMP), right to left ventricle diameter ratio (RV/LV ratio) and computed tomography (CT) obstruction score. The secondary outcomes were all-cause and cardiovascular mortality, major and minor bleeding episodes and recurrent PE. The 11 trials (n=553) and 15 trials (n=655) met eligibility criteria of primary and secondary outcomes, respectively. USAT was found to significantly reduce PAMP, RV/LV ratio and CT obstruction scores. After adjusting for baseline covariates in meta-regression analysis, male sex and number of high-risk patients were found to be associated with PAMP and RV/LV ratio while only male sex was associated with CT obstruction scores. The pooled incidence of all-cause and cardiovascular mortality were 3.2% and 2.2%, and the incidence of major and minor bleeding episodes were 5.5% and 6.9%, respectively. In the pooled analysis of the remaning trials, the incidence of recurrent PE was 1.7%. USAT compared with three randomized thrombolytic trials showed a similar death rate with a lower rate of major bleeding. Conclusion: This meta-analysis confirmed that USAT significantly reduced PAMP, RV/LV ratio and CT obstruction scores with similar death rates and a lower risk of major bleeding compared with patients with PE undergoing systemic thrombolytic treatment.

Background: Sunitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF), is approved for first and second line treatment of advanced renal cell carcinoma (RCC). Knowledge on the effects of sunitinib on cardiovascular (CV) risk and renal damage is limited. Aim: To evaluate possible renal and CV damage in patients with RCC treated with sunitinib. Materials and Methods: Patients with metastatic RCC treated with sunitinib were enrolled. This population was evaluated before starting treatment (T0) and after 3 months (T1). Laboratory and instrumental parameters, including interventricular septum (IVS) and left ventricular mass index (LVMI) were recorded before and after treatment. Results: Thirty-two patients (13 female, 19 male, mean age 62.7±9.9 years) were enrolled. We observed overtime, a significant reduction in estimated glomerular filtration rate (eGFR) (p=0.01), hemoglobin (Hb) (p=0.04) and 25-hydroxyvitamin D (25-OH-VitD) (p=0.002), in association with a significant increase in serum phosphorus (p<0.001), systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001), IVS (p=0.03) and proteinuria (p<0.001), while we showed no significant differences in glycosuria, phosphaturia, serum uric acid, intact parathormone, and LVMI. Conclusion: We observed the development of renal damage and worsening of CV indices in patients treated with sunitinib. We suggest to consider a careful assessment of renal function and CV risk factors, before initiation and during administration of this drug.

Background: Single-pill fixed dose combination (FDC) therapies are widely used in the treatment of arterial hypertension. Objective: This pilot study aimed to evaluate the effects of a FDC therapy combined with therapeutic drug monitoring (TDM) on blood pressure (BP) in patients with treatment resistant hypertension. Method: The study population included patients with suspected treatment-resistant hypertension during treatment with at least 3 antihypertensive drugs. We evaluated the effect of switching all patients to a regime including a single-pill triple FDC containing olmesartan, amlodipine and hydrochlorothiazide. Adherence was evaluated by measuring serum concentrations of amlodipine in a single-blinded fashion. Results: We enrolled 13 patients (mean age 57.2±9.1 years, 8 males) with resistant hypertension (office systolic and diastolic BP 158.3±17.3 and 94.8±11.1 mmHg); mean use of antihypertensive drugs was 3.8±1.1. Medication intake of FDC was confirmed in all patients at 18 weeks. Systolic and diastolic office BP were significantly lower (-22.8 and -13.6 mmHg) after 18 weeks of treatment with triple FDC (135.5±20.1 and 81.2±6.3 mmHg, p<0.01, respectively); mean use of antihypertensive drugs was 3.8±0.9. In 9 patients with 24-h ambulatory BP monitoring (ABPM) both at baseline and after 18 weeks, 24-h mean arterial pressure decreased (-9.3 mmHg, p=0.055). Overall, 9 (69%) patients achieved BP control in office BP and 4 (31%) in 24-h ABPM. Conclusion: Our results support the use of single-pill triple FDC therapy in combination with TDM for the management of patients with suspected treatment-resistant hypertension and further testing in clinical studies.