Current Pharmaceutical Design - Volume 23, Issue 31, 2017

Background: In patients with diabetes mellitus (DM) there is a clear association between blood pressure (BP) levels and macrovascular and microvascular complications. However, the BP targets that need to be achieved for optimal outcomes remain controversial. Methods: The purpose of this narrative review is to discuss BP targets and management in patients with DM. The subject of elevated heart rate, which has been associated with mortality in many populations, and which is observed in some patients with DM will also be addressed. Results: Most guidelines recommend a target BP in patients with DM of <140/90 mmHg. Most consistently recommended first-line pharmacotherapy for the treatment of hypertension in non-black patients with DM is an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) while for black patients a calcium channel blocker or a thiazide diuretic. Newer antidiabetic drugs, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose co-transporter-2 (SGLT2) inhibitors lower not only blood glucose but also BP levels. The SGLT2 inhibitor-associated decrease in BP is not accompanied by an increase in heart rate, which is observed however with GLP-1 receptor agonists. Conclusion: The most widely accepted BP target for patients with DM among guidelines is <140/90 mmHg and the most widely accepted pharmacotherapy to achieve these goals are ACE inhibitors and ARBs. Newer antidiabetic medications have been shown to also lower BP and decrease cardiovascular events, thus representing a promising new therapeutic option for patients with DM and hypertension.

Background: Stroke represent one of the most devastating of all neurological diseases, affecting about 15 million people per year and is an important cause of morbidity and mortality worldwide and currently the leading cause of adult disability in developed countries. Blood pressure and heart rate may undergo several modifications in patients with both ischemic and hemorrhagic stroke in fact raised blood pressure levels may lead to cerebral edema, hematoma expansion or hemorrhagic transformation and in contrast low blood pressure can lead to increased cerebral infarction or perihematomal ischemia. In addition, ECG abnormalities and cardiac arrhythmias, especially atrial fibrillation, are relatively frequent after stroke, and other well known complications such as heart failure, miocardial infarction and sudden death have been reported. The acute phase of brain infarction requires a careful management of both blood pressure levels and heart rate but despite the large amount of information, blood pressure and heart rate management are still under debate. Objective: Provide clear indications about the optimal blood pressure and heart rate management of both ischemic and hemorrhagic stroke, in view of the main available evidence. Method: In this review, we discuss the evidence for blood pressure and heart rate management in acute stroke, the challenges and issues raised, and look to on-going and future trials that may provide some clarity in this controversial area.

Background: Arterial hypertension (AH) and peripheral arterial disease (PAD) frequently coincide. While significant attention is paid to AH, PAD is often underestimated. It is known that both AH and PAD present high cardiovascular risks for ischemic events. To date, the use of the most common anti-hypertensive drugs in PAD patients is still under debate. Methods: Data from studies of large populations and minor cohorts of patients show AH and PAD together or PAD alone. Results: cardiovascular and renal outcomes for PAD patients show lowered arterial pressure. We cannot rank the class of anti-hypertensive drugs recommended for PAD patients with AH. However, optimum targeted anti-hypertensive therapy is strongly recommended by cardiology guidelines. Conclusion: comprehensive cardiovascular protection is the most important goal in using anti-AH drugs in PAD together with other drugs such as anti-platelets and statins.

Background: Hypertension is considered a major health problem in patients with chronic kidney disease (CKD) as approximately 80-85% of CKD patients’ suffer from hypertension in the United States. Hypertension is the second leading cause of CKD after diabetes and is strongly related to morbidity and mortality. It has been found that there is a relation among hypertension, glomerular filtration rate (GFR) and creatinine levels. Objective: Since there is a strong relation between hypertension and CKD, and hypertension seems to lead to cardiovascular diseases, which have epidemic proportions in CKD, this review article discusses the etiology of hypertension and the existing optimal therapies that contribute to the hypertension and heart rate management. Results: There are many approaches that contribute to the management of hypertension and heart rate in CKD patients. Lifestyle modifications in combination with drug therapy lead to the better control of hypertension in CKD patients. Conclusion: Hypertension is strongly related to cardiovascular diseases in CKD patients. Since this relation exists and hypertension leads to cardiovascular diseases, the management of hypertension and increased heart rate should be a main therapeutic target in these patients.

Background: Heart failure (HF) is a global health problem. Like most chronic diseases, HF also courses with acute exacerbations, which have been found to be associated with significant morbidity and mortality. A substantial proportion of acute decompensated heart failure (ADHF) patients clinically present with volume overload. Methods: The goal of this work was to review the current literature and recent guidelines of European Society of Cardiology and American Heart Association/ American College of Cardiology regarding the management strategies in patients with ADHF and volume overload. Results: In the setting of ADHF and volume overload, prompt diagnosis of the disease should be made. Underlying pathologies should be identified and corrected if possible. Specific approaches may be necessary depending on the etiology. Discussion: Current guidelines direct clinicians on the appropriate principles of management in this group of patients; however, approach should be individualized.

Background: New insights on the relationship between weight loss and hypertension and the role of the newly approved anti-obesity drugs on hypertension will be discussed Methods: Weight loss is a major factor to reduce blood pressure when a patient with excess weight is advised from the health care provider to change his lifestyle. A healthy lifestyle with reduction in body weight, reduction in caloric intake, increased fruit and vegetables consumption and reduced salt intake concomitant with an increase in physical exercise can reduce body weight and hypertension in overweight and obese patients, but not all obese are able to reduce their blood pressure and lose weight without treatment and special dietary care. Moreover, most obese people lose weight for a small period and then they regain all the weight that they have lost or even worse, they increase their weight more than before starting a diet. Newly-approved weight loss drugs have variable actions on high blood pressure. Liraglutide and phentermine/topiramate seem to reduce hypertension, while after the bupropion/naltrexone or lorcaserin use trials reported a rise in blood pressure. Conclusion: Reduction in body weight with treatment is not always associated with reduction in obesity induced hypertension. Weight loss treatments that exhibit sympathomimetic or adrenergic actions should be used with care and for short periods of time.

Background: The importance of increased resting heart rate in hypertensive patients was highlighted in the European Society of Hypertension statement on the identification and management of hypertensive patient with elevated heart rate. Methods: Review of the available literature. Results: Increased heart rate is an independent predictor of cardiovascular morbidity and mortality even after adjustment for other conventional cardiovascular risk factors. Resting heart rate is correlated with blood pressure and prospectively related to the development of hypertension, as shown in numerous general population and hypertensive cohorts. Patients with hypertension may be characterized by increased sympathetic activation, and increased heart rate is considered a simple marker of increased sympathetic nervous activity. The definition of tachycardia is debatable as in clinical practice, tachycardia is generally defined as resting heart rate over 100 beats per minute (bpm) but this definition does not take into account epidemiological data and risk related to increased heart rate. Available evidence suggests that a lower threshold defining an increased resting heart rate should be adopted. In large hypertensive cohorts, approximately one third of the studied subjects had resting heart rate above 80-85 bpm and many of these patients had features of the metabolic/insulin resistance syndrome. Furthermore, the prevalence of hypertension increases with age and the hemodynamic pattern of hypertension in older subjects is not characterized by increased heart rate. Conclusions: These reasons, in addition to the fact that heart rate is variable and depends on multiple factors, may explain why not all patients with hypertension are tachycardic at rest.

Background: Clinic resting heart rate (RHR), is one of the cardiovascular parameters more easily measurable. In the general population RHR has been associated with total and cardiovascular mortality and higher rate of vascular events. Objective: The case of essential hypertension is in some ways peculiar: in the past decades has often been attributed to hypertensive subjects higher values of RHR than healthy controls as a result of the effects of the different factors leading to the development of essential hypertension itself, first of all the presence of an increased tone of the sympathetic nervous system Methods: Several excellent articles debated the issue of autonomic dysfunction in essential hypertension; nevertheless of this, after various decades of debate, this issue is to-date unresolved. The aim of this review is to discuss the reliability of the hypothesis that elevated resting heart rate in hypertensive subjects is associated to high blood pressure and both to elevated sympathetic nervous system activity or rather if these three phenomena coexist in a limited portion of subjects being not necessarily linked each other with a causal relationship. Results: The ascertainment of the exact proportion of the hypertensive subjects having sympathetic overdrive appears to be hard, not only due to the multiple interferences and the constant interplay between the various determinants of the sympathetic tone, but also because a significant uncertainty remains with regard to the validity of the methods used for assessing the sympathetic tone. Conclusions: To date, any threshold used to define tachycardia is arbitrary. The percentage of hypertensive patients with elevated RHR varies considerably between the various studies, first of all because the modality of assessment influences the results. The “white coat tachycardia” is a clinical entity that must be taken into account. Ambulatory heart rate represents a good diagnostic alternative, since nocturnal mean heart rate appears to be the parameter with the highest prognostic value, probably because is less conditioned by external factors, being more representative of the “real” heart rate of the subject.

It was initially assumed that heart rate and arterial blood pressure were modulated by normal respiration and muscle contraction. The arterial baroreflex, an inverse relationship between blood pressure and heart rate, was later reported. Nonetheless, it was then assumed that those responses involved vagal modulation. We summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on blood pressure (BP) control. Numerous studies have tried to clarify whether aerobic exercise modifies neurally-mediated vasoconstriction, but they report contradictory results. In view of these incongruities, the aim of this narrative review is to summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on BP control. We mainly focus on the effects of aerobic exercise in both heart rate and blood pressure. Heart rate and heart rate variability have been indistinctly considered similar metrics, but they have completely different meanings when properly used. Both are risk markers in cardiac disease, whereas heart rate variability is also an index of sympathovagal modulation of heart rate. On the other hand, heart rate recovery has been also used as an index for mirroring both cardiovascular fitness and autonomic function, and can be used as a measure of vagal reactivation. Importantly, it is now wellknown that a reduced rate of heart rate recovery represents a powerful predictor of overall mortality. In this review, due to its complexity, we have included studies in which any of these three parameters have been analyzed.

Objective: This review covers the pharmacokinetics and pharmacodynamic of β-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation β-blockers beyond hypertension. Background: The efficacy and safety of β-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of β-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that β-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating β-blockers (atenolol and metoprolol) are inferior to first-line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism. Conclusion: New vasodilating β-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs. nonvasodilating β-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation β-blockers are superior to conventional β-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation β-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a “promissory new era” of this newly group.

Background: Results of previous clinical trials evaluating the effect of magnesium supplementation on inflammatory markers are controversial. Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to evaluating the effect of oral magnesium supplementation on plasma C-reactive protein (CRP) concentrations. Method: PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (from inception to August 09, 2016) to identify RCTs, evaluating the effect of magnesium on CRP levels. A random-effects model and a generic inverse variance method were used to compensate for the heterogeneity of studies. Publication bias, sensitivity analysis, and meta-regression assessments were conducted using standard methods. Results: Overall, the impact of magnesium supplementation on plasma concentrations of CRP was assessed in 11 studies. Magnesium treatment was not found to significantly affect plasma concentrations of CRP (WMD: -0.11 mg/L, 95% CI: -0.75, 0.52, p=0.727). When the analysis was stratified to compare subgroups of studies in populations with baseline plasma CRP values of ≤ 3 and > 3 mg/L, a significant reduction of CRP values was observed in the latter subgroup (WMD: -1.12 mg/L, 95% CI: -2.05, -0.18, p=0.019) but not in the former group (WMD: 0.61 mg/L, 95% CI: -0.10, 1.32, p=0.090). The difference between subgroups was statistically significant (p=0.004). Conclusion: Results of the present meta-analysis indicated that magnesium supplementation reduces CRP levels among individuals with inflammation (CRP levels > 3 mg/dL). This finding suggests that magnesium supplements may have a beneficial role as an adjuvant for the management of low-grade chronic systemic inflammation.

Efforts to develop and refine percutaneous approaches to cardiac valve repair and replacement have advanced rapidly over the past several years, having exceeded even the most optimistic expectations. New innovations have been predominantly directed toward the most frequent form of valvular heart disease (VHD) in the industrialized world; aortic stenosis (AS). Approximately 250,000 transcatheter aortic valve implantation (TAVI) procedures have been done so far addressing this significant medical need. Because of the predominance of degenerative etiologies, the prevalence of VHD increases markedly in population above the age of 65 years, in particular with regard to severe AS. As the populations of the industrialized countries continue to be older, the need for less invasive and safer methods of treating severe AS will continue to grow. In this review we provide comprehensive and up-to-date overview of TAVI in current clinical practice. We have also addressed dilemmas and unanswered questions related to TAVI procedures in different groups of patients and highlighted opportunities and trends related to future TAVI implementation.

This review focuses on the biological role and clinical relevance of relatively poor studied enzymes known as sialidases. We describe structure and function of sialic acid, in particular as a component of gangliosides and plasma lipoproteins. Several types of sialidases are known in mammals, of which trans-sialidase is of special interest, since it is capable of removing sialic acid from low density lipoprotein (LDL) particles and transferring it to different acceptors in blood plasma. Desialylation of LDL, in turn, endows it a capacity to accumulate in the smooth muscle cells of human aortic intima, and therefore is important for atherogenesis. Moreover, sialidases appear to be involved in a variety of pathological processes, including viral infections and cancer, which makes these enzymes an attractive therapeutic target.