The potential effect of natural antioxidants on endothelial dysfunction associated with arterial hypertension.

Arterial hypertension represents a leading cause of cardiovascular morbidity and mortality worldwide, and the identification of effective solutions for treating the early stages of elevated blood pressure (BP) is still a relevant issue for cardiovascular risk prevention. The pathophysiological basis for the occurrence of elevated BP and the onset of arterial hypertension have been widely studied in recent years. In addition, consistent progress in the development of novel, powerful, antihypertensive drugs and their appropriate applications in controlling BP have increased our potential for successfully managing disease states characterized by abnormal blood pressure. However, the mechanisms responsible for the disruption of endogenous mechanisms contributing to the maintenance of BP within a normal range are yet to be fully clarified. Recently, evidence has shown that several natural antioxidants containing active ingredients originating from natural plant extracts, used alone or in combination, may represent a valid solution for counteracting the development of arterial hypertension. In particular, there is evidence to show that natural antioxidants may enhance the viability of endothelial cells undergoing oxidative damage, an effect that could play a crucial role in the pathophysiological events accompanying the early stages of arterial hypertension. The present review aims to reassess the role of oxidative stress on endothelial dysfunction in the onset and progression of arterial hypertension and that of natural antioxidants in covering several unmet needs in the treatment of such diseases.

Single-Pill Combination with Three Antihypertensive Agents to Improve Blood Pressure Control in Hypertension: Focus on Olmesartan-Based Combinations.

Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require combination and double or triple therapies. International guidelines recommend the association of drugs with complementary mechanisms of action and, in particular, the combination of renin-angiotensin system (RAS) inhibitors, calcium channel blockers (CCBs), and diuretics. Among the various angiotensin receptor blockers, olmesartan (OM) is available as a monotherapy and in dual and triple single-pill combinations (SPCs) with amlodipine (AML) and/or hydrochlorothiazide (HCTZ). Several phase III and IV studies, together with real-world studies, have demonstrated the additional benefits of combining OM either with AML or with HCTZ in terms of BP control and target BP achievements both in the general population and in special subgroups of hypertensive patients, such as the elderly, diabetic, chronic kidney disease or obese patients. Ambulatory BP monitoring studies assessing 24h BP have also demonstrated that dual, as well as triple, OM-based SPCs induce a more sustained and smoother BP reduction than placebo and monotherapy. Furthermore, triple OM-based SPC has been shown to improve therapeutic adherence in hypertensive patients compared to free combinations. The availability of OM combined with HCTZ, AML or both at different dosages makes it a valuable option to customize therapy based on the levels of BP and the clinical characteristics of hypertensive patients.

Overview of mitral valve replacement versus mitral valve repair due to ischemic papillary muscle rupture: A meta-analysis inspired by a case report.

BACKGROUND: Papillary muscle rupture (PMR) is an infrequent but catastrophic complication after myocardial infarction (MI). Surgical procedure is considered the optimal treatment, despite high risk. However, the gold standard technique is still a major dilemma. Therefore, a meta-analysis was carried out to assess and provide an overview comparing mitral valve replacement (MVR) and mitral valve repair (MVr) for PMR post-MI. METHODS: A systematic literature search was performed. Data were extracted and verified using a standardized data extraction form. Meta-analysis was realized mainly using RevMan 5.4 software. RESULTS: From four observational studies 1640 patients were identified; 81% underwent MVR and 19% MVr. Operative mortality results were significantly higher in MVR group than the MVr group. MVR was performed under emergency conditions and patients admitted in cardiogenic shock or who required the use of mechanical cardiac support underwent MVR. MVr had shorter time of hospitalization and similar incidence of postoperative complications than MVR. No significant differences existed between the two procedures regarding cardiopulmonary bypass time. CONCLUSIONS: Mitral valve repair appears to be a viable alternative to MVR for post-MI PMR, given that it has lower operative mortality, shorter time of hospitalization and similar incidence of short-term postoperative complications than MVR. However, it needs to be pointed out that MVR was associated with the most critical clinical condition following PMR. There is uncertainty regarding the overall survival and improvement of the quality of life between the procedures. Nevertheless, further completed investigation is required.

Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction.

BACKGROUND: Trehalose (TRE) is a natural, nonreducing disaccharide synthesized by lower organisms. TRE exhibits an extraordinary ability to protect cells against different kinds of stresses through activation of autophagy. However, the effect of TRE on the heart during stress has never been tested. OBJECTIVES: This study evaluated the effects of TRE administration in a mouse model of chronic ischemic remodeling. METHODS: Wild-type (WT) or beclin1+/- mice were subjected to permanent ligation of the left anterior descending artery (LAD) and then treated with either placebo or trehalose (1 mg/g/day intraperitoneally for 48 h, then 2% in the drinking water). After 4 weeks, echocardiographic, hemodynamic, gravimetric, histological, and biochemical analyses were conducted. RESULTS: TRE reduced left ventricular (LV) dilation and increased ventricular function in mice with LAD ligation compared with placebo. Sucrose, another nonreducing disaccharide, did not exert protective effects during post-infarction LV remodeling. Trehalose administration to mice overexpressing GFP-tagged LC3 significantly increased the number of GFP-LC3 dots, both in the presence and absence of chloroquine administration. TRE also increased cardiac LC3-II levels after 4 weeks following myocardial infarction (MI), indicating that it induced autophagy in the heart in vivo. To evaluate whether TRE exerted beneficial effects through activation of autophagy, trehalose was administered to beclin 1+/- mice. The improvement of LV function, lung congestion, cardiac remodeling, apoptosis, and fibrosis following TRE treatment observed in WT mice were all significantly blunted in beclin 1+/- mice. CONCLUSIONS: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.

Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases.

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases.

New therapies for arterial hypertension.

Arterial hypertension is the most common chronic disease in developed countries and it is the leading risk factor for stroke, ischemic heart disease, congestive heart failure, chronic renal failure and peripheral artery disease. Its prevalence appears to be about 30-45% of the general population. Recent European guidelines estimate that up to 15-20% of the hypertensive patients are not controlled on a dual antihypertensive combination and they require three or more different antihypertensive drug classes to achieve adequate blood pressure control. The guidelines confirmed that diuretics, beta-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in combination therapy. Very few antihypertensive agents have reached the market over the last few years, but no new therapeutic class has really emerged. The long-term adherence to cardiovascular drugs is still low in both primary and secondary prevention of cardiovascular diseases. In particular, the issue of compliance is persistently high in hypertension, despite the fixed-dose combination therapy. As a consequence, a cohort of high-risk hypertensive population, represented by patients affected by refractory and resistant hypertension, can be identified. Therefore, the need of controlling BP in high-risk patients may be addressed, in part, by the development of new drugs, devices and procedures that are designed to treat hypertension and comorbidities. In this review we will comprehensively discuss the current literature on recent therapeutic advances in hypertension, including both medical therapy and interventional procedures.

Eligibility for the Subcutaneous Implantable Cardioverter-Defibrillator in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: High-risk hypertrophic cardiomyopathy (HCM) patients benefit from the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) may provide comparable protection while avoiding the shortcomings of transvenous (TV) leads. We assessed S-ICD eligibility according to surface ECG screening test in a cohort of high-risk HCM patients. METHODS AND RESULTS: 47 HCM patients (3 S-ICD candidates; 41 TV-ICD patients without pacing indication; and 3 pacemaker-dependent TV-ICD patients) underwent 4 screening protocols: standard (n = 44); exercise (n = 33); continuous pacing (n = 44); alternating paced/spontaneous QRS (n = 41). Of the 44 patients in the standard screening group, 41 (93%) were eligible. Max LV thickness was inversely related to the number of qualifying leads (3 leads: 21 ± 4 mm; 2 leads: 22 ± 6 mm; 1 lead: 25 ± 6 mm; no leads: 28 ± 11 mm; P = 0.07). Of the 33 patients in the exercise group, 5 were ineligible (3 after exercise). Of these, 2 became eligible after moving sternal electrodes from the left to the right parasternal line (eligibility rate: 30/33; 91%). Of the 44 patients in the continuous pacing group, 28 (64%) were eligible, 8 of which with right parasternal electrodes. In the paced/spontaneous QRS group (n = 41), 21 patients (51%) had at least 1 eligible lead during pacing and retained compatibility on the same lead during spontaneous rhythm, 5 of which with right parasternal electrodes. CONCLUSIONS: S-ICD screening failure is low in HCM, provided that patients with severe hypertrophy are carefully evaluated. Exercise test should be performed and right parasternal leads tested. Pacemaker patients display lower eligibility rate.

Integrated preclinical cardiovascular prevention: a new paradigm to face growing challenges of cardiovascular disease.

Cardiovascular disease (CVD) still represents the leading cause of mortality and morbidity worldwide. Despite considerable improvements in the prognosis of CVD and the significant reduction of CVD mortality obtained during the past half century, patients developing CVD, even though satisfactorily treated, still carry coronary artery disease and remain at risk for advanced CVD. Thus, the healthcare and socioeconomic burden linked to CVD remains high. As a result, more effective CVD prevention strategies remain crucial. 'Population strategies' and 'high-risk' approaches both have limitations and have often been viewed as alternative solutions. This persistent dualism could be overcome with the promotion of integrated prevention strategies based on a systematic evaluation of the total risk of disease, at both a population and an individual level. New approaches are also needed to reach people earlier in the course of the vascular disease and, possibly, to prevent risk factors and reduce CVD clinical manifestation.

Hypovitaminosis D and organ damage in patients with arterial hypertension: a multicenter double blind randomised controlled trial of cholecalciferol supplementation (HYPODD) : study design, clinical procedures and treatment protocol.

INTRODUCTION: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature. AIM: To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage). METHODS: HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona). RESULTS AND CONCLUSION: The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.

Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARα/UCP2 axis.

OBJECTIVES: Renal damage precedes occurrence of stroke in high-sodium/low-potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)/peroxisome proliferator-activated receptor-α (PPARα)/UCP2 axis. METHODS: SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARα inhibitor (GW6471). A group of SHRSP fed with regular diet served as control. RESULTS: Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARα inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells. CONCLUSION: B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1α/PPARα/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension.

Modern clinical management of arterial hypertension: fixed or free combination therapies?

Blood pressure control is a key element in any cardiovascular prevention strategy. However, it is also one of the least frequently achieved goals in modern strategies for the clinical management of cardiovascular diseases, resulting in high impact in terms of cardiovascular morbidity and mortality. Among different factors that can be identified as the causes of poor blood pressure (BP) control in the general population of patients with hypertension, the excessive use of monotherapy, as opposed to combination therapy, is arguably one of the most significant. In this perspective, the use of combination therapies having synergic and complementary actions has been shown to reduce BP levels to increase the percentage of patients who respond to antihypertensive treatment and achieve the recommended BP targets. Moreover, recent studies have demonstrated that these strategies provide effective protection against hypertension-related organ damage, as well as a significant reduction of major cardiovascular events. While currently available evidence supports an increasingly important role of combination therapies compared with monotherapies, several other issues remain to be clarified. Among these, it has not yet been clearly established which classes of drugs should be considered for combination strategies, at what doses each component should be used, and whether combination strategies may be definitively considered as a first choice for the treatment of hypertensive patients at cardiovascular risk. Another relevant aspect concerns the choice between fixed and free combination therapies. This article discusses and analyses the different factors that may contribute to achieve effective BP control. In particular, the potential benefits and drawbacks associated with the use of fixed versus free combination therapies for hypertension treatment will be examined and discussed. The benefits of using combination strategies based on drugs that antagonize the renin-angiotensin system and dihydropyridine calcium antagonists will also be discussed, with a particular focus on amlodipine besylate combination therapies.

Non-pharmacological control of plasma cholesterol levels.

The importance of non-pharmacological control of plasma cholesterol levels in the population is increasing, along with the number of subjects whose plasma lipid levels are non-optimal, or frankly elevated, according to international guidelines. In this context, a panel of experts, organized and coordinated by the Nutrition Foundation of Italy, has evaluated the nutritional and lifestyle interventions to be adopted in the control of plasma cholesterol levels (and specifically of LDL cholesterol levels). This Consensus document summarizes the view of the panel on this topic, with the aim to provide an updated support to clinicians and other health professionals involved in cardiovascular prevention.

Role of a molecular variant of rat atrial natriuretic Peptide gene in vascular remodeling.

Previous studies in a hypertensive animal model of stroke and in humans showed that mutations of the atrial natriuretic peptide (ANP) gene are associated with increased risk of stroke. To elucidate the vascular disease mechanisms that result from structural modifications of the ANP gene, we investigated a coding mutation of the ANP gene in stroke-prone spontaneously hypertensive rats (SHRsp). This mutation leads to a Gly/Ser transposition in the prosegment of ANP. We found that presence of this mutation is associated with increased immunostaining of ANP in the wall of SHRsp cerebral vessels. The mutation causes a major inhibitory effect on endothelial cell proliferation, as assessed by thymidine incorporation, and on angiogenesis, as determined by an endothelial cell tube formation assay, in human umbilical vein endothelial cells (HUVEC) exposed to ANP/SHRsp. These in vitro findings show that the SHRsp-derived form of ANP has an inhibitory effect on vascular remodeling and they provide further support for a role of the ANP gene in the pathogenesis of cerebrovascular disease in the animal model.