Current Vascular Pharmacology - Volume 16, Issue 1, 2018

Background: Hypertension (HT), albeit a modifiable risk factor of cardiovascular morbidity and mortality, remains one of the main contributors to the total disease burden internationally and, thus, inevitably one of the basic cost drivers in healthcare systems. Conclusion: Taking the above into account, this brief narrative review aims at presenting the main findings of the international health economics literature on HT with regards to four key areas: a) the costs attributable to HT, b) the effects of HT on patient well-being, c) the cost-effectiveness of pharmaceutical interventions against high blood pressure, and, d) the costs and benefits of preventive measures against HT. Bearing in mind the available evidence on disease costs and the efficiency of interventions, HT must constitute a primary objective of modern health policy, internationally.

Introduction: Resistant hypertension (HT) is a common clinical entity with debilitating cardiovascular consequences. The highly heterogeneous nature of resistant HT requires a meticulous workup to exclude ‘pseudo-resistance’ and secondary forms of arterial HT. Resistant HT has recently gained wide scientific interest due to the introduction of interventional methods (renal sympathetic denervation and carotid baroreceptor stimulation) for blood pressure (BP) reduction in this patient population. Despite however the recent advances in understanding the pathophysiology and the clinical characteristics of the disease, the appropriate management of resistant HT remains elusive. The marked heterogeneity of BP response to interventional therapy underlines the need for careful patient selection and the identification of ideal candidates for interventional therapy. Conclusion: The renin-angiotensin-aldosterone system seems to play a cardinal role in the pathophysiology of resistant HT and requires appropriate management. Furthermore, primary aldosteronism is considered the most common form of secondary HT, with increased prevalence in patients with resistant HT. This review aims to provide a simplified work-up for patients with resistant HT, summarize the rationale for the determination of renin and aldosterone levels, and critically discuss available evidence on when and how to measure renin/aldosterone in resistant HT.

Introduction: Heart failure (HF) with preserved ejection fraction (EF) (HFpEF) accounts for approximately 50% of HF cases and its prevalence relative to HF with reduced EF is rising. Hypertension (HT) is the most common co-morbidity in HFpEF patients and it is implicated in both the pathogenesis and the prognosis of the disease. Therefore, HT is a modifiable risk factor of high yield in HFpEF. We reviewed the literature for epidemiologic data supporting the co-aggregation of the two entities as well as patho-physiologic mechanisms linking HT to HFpEF. Most importantly, we focused on treatment options targeting HT as a preventive strategy for delaying the progression of diastolic dysfunction or decreasing the odds for developing HFpEF. Conclusion: Along this line, we summarized the evidence and efficacy associated with different classes of antihypertensive medications in HFpEF patients. Finally, non-pharmacological approaches, including renal denervation and lifestyle modifications, to achieve optimal blood pressure (BP) control in HFpEF patients are reported. Unfortunately, no specific antihypertensive treatment has established a major survival benefit in this high risk subjects. Until the results of the efficacy of the novel drug LCZ696 (valsartan/ sacubitril) are available, the continuous monitoring and lowering of the BP by pharmacological and non-pharmacological means should be considered the major preventive and treatment strategy in HFpEF patients.

Introduction: Angiogenesis is fundamental for tumour development and progression. Thus, anti-angiogenic agents have been developed and are mainly vascular endothelial growth factor (VEGF) pathway inhibitors. However, these agents commonly exhibit cardiac and renal toxicity, proteinuria and hypertension (HT). In fact, with the use of anti-angiogenic agents a rapid dose-dependent increase of blood pressure (BP) is observed. The possible mechanisms of VEGF inhibitors-induced HT include systemic endothelial dysfunction, renal impairment as well as vascular micro- and macroangiopathy. Furthermore, the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in these patients results in uncontrolled HT. Conclusion: Lifestyle changes are the cornerstone of antihypertensive treatment. No clear recommendations for a specific antihypertensive agent can be made. In most cases antihypertensive management needs to be individualized to each patient. Calcium channel blockers (CCBs) are considered as first line option, while renin-angiotensin-aldosterone system (RAAS) blockers should be the agents of choice in patients with proteinuria. Centrally acting antihypertensive agents and diuretics can also be used. Careful monitoring is critical during therapy and BP should be assessed every week and before any new cycle or infusion of anti-VEGF therapy. If BP remains uncontrolled anti-VEGF treatment discontinuation should be considered. Withdrawal of anti-VEGF therapy needs also a re-evaluation of antihypertensive therapy since BP will return to the prior baseline levels.

Introduction: An imbalance in the Autonomic Nervous System (ANS) is a central pathophysiologic mechanism in Heart Failure (HF) and has been a principal target of treatment in these patients. Traditional pharmacologic agents do not provide specific modulation of discrete arms of the ANS, while side effects may lead to poor tolerance. Technological advances have provided a series of invasive methods that may provide a focused effect on the ANS in selected patient groups. Renal denervation, initially targeted for patients with resistant hypertension, has given positive preliminary results in terms of heart structure and function. Baroreceptor stimulation also has ongoing research with respect to its efficacy and longer term effects in HF patients. Vagal nerve stimulation and spinal cord stimulation have limited data but represent novel treatments that target the hard to reach parasympathetic system. Conclusion: The present review overviews the pathophysiologic basis, current preclinical and clinical data and future expectations of these promising treatments.

Introduction: Obstructive Sleep Apnoea (OSA) constitutes the most prevalent form of abnormal respiratory control during sleep in adults. Evidence linked OSA to cardiovascular disease, and the role of OSA in abnormal Blood Pressure (BP) control has been extensively studied. Although longitudinal trials suggest a causative role of OSA in the development of hypertension, the evidence is not fully consistent. Nasal continuous positive airway pressure (nCPAP) applied during sleep is well documented and a highly efficient therapeutic aid to eliminate OSA. It has been repeatedly shown that nCPAP-therapy is also associated with modest BP lowering effect in hypertensive OSA-patients, and the magnitude of the observed effect correlates with the severity of OSA. However, it is unlikely that nCPAP would normalize BP. Conclusion: There are few studies which tested the interplay between OSA, nCPAP and certain BPlowering drug classes. Angiotensin receptor blockers may show synergistic hypotensive effect with nCPAP, whereas mineralocorticoid receptor blocker has been shown to modestly attenuate the severity of OSA. Additionally, the application of chronotherapy may be of special use in such patients. The current evidence is sufficient to promote persistent and effective nCPAP-therapy as a standard in all eligible OSA-patients with difficult-to-control hypertension.

Hypertension (HT) is present in more than 80% of patients undergoing Hemodialysis (HD). Elevated Blood Pressure (BP) in hemodialysis patients is associated with cardiovascular events and mortality only when BP is recorded with home or ambulatory monitoring, since pre- and post-dialysis measurements are not valid estimates of BP levels during the interdialytic interval. Sodium and water overload is the most important of several mechanisms involved in HT development in HD. In this context, non-pharmacologic measures to ensure water and sodium balance by achieving patient dry weight and decreasing daily sodium intake, through modification of sodium level in the diet or in dialysis dialysate, are fundamental for HT control. After these strategies are properly implemented, the introduction of drug treatment can further help in achieving optimum BP. All major antihypertensive classes, with the exception of diuretics, can be considered in HT management, as current evidence suggest that the use of agents from these classes was associated with reduced cardiovascular risk. The choice of a specific antihypertensive drug should be based on the co-morbid conditions of the patient, and the pharmacologic characteristics of the agent, including dialyzability. Of note, the need of increasing the number of antihypertensive drugs, should be each time balanced against reappraisal of the non-pharmacologic measures, as increased antihypertensive efficacy can result in a vicious circle of more difficulties regarding dry weight reduction, possible volume overload, and further BP increase.

Fixed-dose triple drug combinations represent one of the latest innovations of pharmacotherapy for hypertension (HT). They combine a traditional renin-angiotensin system blocker, a diuretic and a calcium channel blocker. The main benefit is the simplification of treatment regimen because 3 different agents are combined at different doses in a single pill. Improving adherence to treatment partly explains why this kind of combination may effectively reduce blood pressure (BP). BP lowering by a single- pill triple-drug combination can be approximately predicted, by using appropriate formulas described in previous meta-analysis of randomized trials. Thus, clinicians may select the appropriate dose for each of the combined drugs. Selection of different types of fixed-dose triple-drug combinations relies upon clinical experience, commercial availability and evidence from clinical trials and metaanalyses for each agent alone. However, triple fixed-dose drug combinations should be reserved only for patients with uncontrolled BP with 2 agents, poor adherence in complex therapeutic regimens or on inappropriate free-drug combinations. Also, triple therapy may help overcome clinical inertia by prescribing more potent antihypertensive formulations in one pill. In contrast, this type of multiple-drug fixed-dose combination might be less safe in very old and frail patients, as well as in those with chronic kidney disease. Although new combinations may help overcome the clinical inertia of achieving individualized BP targets, doctors should also pay attention reinforcement of lifestyle changes.

Introduction: Although the first results from studies suggested important benefits regarding blood pressure (BP) control in resistant hypertension by the use of diverse systems of renal denervation (RDN) in the setting of resistant hypertension, the Symplicity HTN-3, randomized sham-controlled trial reduced the enthusiasm and led to a more critical approach towards this neuromodulation innovative therapy. Nowadays there is an ongoing research attempt to justify the pathophysiological background of RDN since overdrive of the sympathetic nervous system is one of the key mechanisms leading to the development and progression of the hypertensive and cardiovascular diseases. Conclusion: Future RDN trials based on the clinical findings and gaps from previous works will try to identify those parameters to help identify better BP response, target the most suitable population and conclude whether this interventional approach can contribute to the clinical problem of uncontrolled hypertension.

Background: The prevalence of Type 2 Diabetes Mellitus (T2DM) is increasing worldwide; this is stimulating more research into the optimal management of this disease. Cardiovascular Disease (CVD) remains the commonest cause of death in individuals with T2DM. Besides hyperglycaemia, an explanation for the increased mortality in this population is the increased prevalence of comorbidities, such as hypertension and dyslipidaemia. Recent population-based studies described a prevalence of hypertension >80% in patients with T2DM. In the last decade new classes of antidiabetic medications have been developed that are effective not only for the management of hyperglycaemia and but also for tailoring treatment according to individual needs and characteristics. Regulatory authorities demand the new antidiabetic medications to be examined for Cardiovascular (CV) safety. Interestingly it has been shown, mainly through CV safety trials, that some new antidiabetic medications not only have glucose lowering effects, but also Blood Pressure (BP) lowering effects, contributing to CV risk reduction. Conclusion: This review considers the effect of older and newer antidiabetic medications on BP in patients with T2DM.

Background: Substantial improvements have been achieved with percutaneous coronary intervention (PCI) for the treatment of Acute Coronary Syndromes (ACS). Nevertheless, bleeding still affects outcomes. The radial approach for PCI has shown important benefits on access site complications, but is still not achieving universal consensus as first choice in acute settings. Therefore, we performed a comprehensive meta-analysis of randomized trials comparing radial vs femoral approach in PCI for ACS. Methods: The literature and main scientific session abstracts were scanned for randomized studies comparing radial vs femoral approach for PCI in ACS. Primary endpoint was mortality within 30-days. Secondary endpoints were: 1) Major Adverse Cardiovascular Events (MACE), 2) major bleeding, and, 3) vascular complications. Results: We included 17 randomized trials, enrolling 19325 patients. A total of 9635 patients were randomized to the radial approach and 9690 to the femoral approach. The radial approach was associated with a significant reduction in mortality (1.8 vs 2.5%, odds ratio, OR [95% CI] = 0.72 [0.59,0.88], p = 0.001, pheterogeneity = 0.31) and in major bleeding complications compared with the femoral approach (1.5 vs 2.6%, OR [95% CI] = 0.57 [0.47, 0.71], p < 0.00001, pheterogeneity = 0.59), with similar advantages observed for both ST-elevation myocardial infarction and non-ST segment elevation ACS. MACE occurrence and vascular complications were also reduced with the radial approach (OR [95% CI] = 0.82 [0.74, 0.92], p = 0.0005, and OR [95% CI] = 0.52 [0.47, 0.58], p < 0.00001, respectively). Our results were not influenced by patient risk profile or the antithrombotic strategy applied. Conclusion: Our meta-analysis shows that among ACS patients undergoing PCI, the radial approach is associated with a significant reduction in mortality, major bleeding complications, MACE and vascular complication compared with the femoral approach.

Aims: Nitroxyl anion (HNO) has recently become an emerging candidate in vascular regulation. NO- is a potent vasodilator of both conduit and small resistance vessels and mediates relaxation in a soluble guanylate cyclase-dependent manner. Interestingly, HNO activates voltage-dependent K+(K+V) channels, whereas Nitric Oxide (NO) activates calcium-activated K+Ca channels. To date, there are few studies investigating the role of HNO in hypertension, and the possible mechanisms, which may be altered during this condition. We hypothesized that mesenteric arteries from angiotensin II-induced (AngII) hypertensive mice would exhibit an increased dependence upon NO- for relaxation, which may be mediated through K+V channels. Methods and Key Results: C57/Bl6 mice, aged 12-14 weeks were implanted with mini-pumps containing angiotensin II (AngII, 3600ng/kg/min) for 14 days. For this study, we proposed to investigate the role of HNO in the resistance vasculature, and so first order mesenteric arteries were isolated and used in functional studies, or were frozen for Western blot analysis. We observed that mesenteric arteries from AngII mice (AngII) exhibited a decrease in HNO-mediated relaxation, which was endotheliumindependent. With HNO scavenging by L-cysteine [3mM], the maximal acetylcholine (ACh)-mediated relaxation response was decreased in sham, whereas mesenteric arteries from AngII exhibited a decrease in sensitivity. Incubation with the K+V channel inhibitor, 4-aminopyridine [1mM], decreased AChmediated relaxation responses in sham, but almost completely abolished relaxation in AngII. Conclusion: We reveal that exogenous HNO-mediated relaxation, via Angeli's Salt, is impaired in mesenteric arteries from AngII-treated mice, yet endogenous HNO-mediated relaxation may be more important during hypertension.