Ranolazine: A true pluripotent cardiovascular drug or jack of all trades, master of none?

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Although the majority of patients with CVD are treated with interventional procedures, a substantial number require medical therapy in terms of both prognosis and symptomatic relief. However, commonly used agents such as ß-blockers and calcium channel blockers reduce blood pressure in patients whose resting pressures are often already low. Ranolazine is a promising agent that does not have significant effects on blood pressure or heart rate. Use of this drug has been documented in various cardiovascular conditions, including ischaemic heart disease, heart failure and arrhythmias. This review article aimed to examine current evidence on the use of ranolazine in various cardiovascular conditions in order to determine whether it is a true pluripotent cardiovascular agent or, on the other hand, a "jack of all trades, master of none."

Matrix metalloproteinases and their tissue inhibitors in hypertension-related pregnancy complications.

Matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade the components of the extracellular matrix (ECM) such as collagen, and thus contribute to the remodelling and the physiological homeostasis of the ECM and its blood supply. The activities of these enzymes are regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and it has been suggested that a balance between MMPs and TIMPs plays an important role in vascular remodelling, angiogenesis and vasodilatation in a number of physiological situations. It follows that, regarding a relationship between MMPs and TIMPs, an imbalance between these molecules may lead to pathology in a wide range of conditions, including hypertension, cancer and pulmonary disease, and in the pathophysiology of reproduction. Indeed, regarding the latter, abnormalities in the maternal peripheral vasculature have been proposed as being (partly) responsible for the effects of hypertension on pregnancy and the development of complications including pre-eclampsia and eclampsia. However, the associations between MMPs, TIMPs and disease may be simply of association, not of pathology. This brief review explores current literature on the role of abnormalities of the ECM in general, focusing on the pathogenesis of hypertension and its complications during pregnancy as a model of disordered angiogenesis and remodelling.

Endothelial dysfunction in hypertension in pregnancy: associations between circulating endothelial cells, circulating progenitor cells and plasma von Willebrand factor.

BACKGROUND: Endothelial damage/dysfunction has been related to hypertension in pregnancy, with implications in pregnancy outcomes. We hypothesised abnormal levels of circulating endothelial cells (CECs), circulating progenitor cells (CPCs) and plasma von Willebrand factor (vWf, a marker of endothelial damage/dysfunction) in pregnant women with hypertension, when compared to pregnant normotensives and non pregnant healthy controls. METHODS: Our study groups were 3rd trimester hypertensive pregnant women, 40 age matched normotensive pregnant women and 50 non pregnant healthy controls. CECs were measured by immunomagnetic separation using anti-CD146 monoclonal antibody coated beads. CPCs were defined using flow cytometry as CD133+/CD34+/CD45-. vWf was measured by ELISA. RESULTS: Hypertensive pregnant women had significantly higher CECs compared to normotensive pregnant women and non pregnant healthy controls (p < 0.001). CPCs were raised in the normotensive pregnant group compared with hypertensive pregnant and non pregnant healthy controls (p < 0.05). Both pregnant women groups had significantly higher vWF than the non pregnant controls. CEC levels correlated with both systolic and diastolic BP (r = 0.28, p < 0.005 and r = 0.31, p < 0.001, respectively). vWf correlated with CECs (r = 0.39, p < 0.0001). Multiple linear regression analysis revealed hypertension in pregnancy as an independent predictor of CEC levels (p < 0.0001). CONCLUSIONS: Hypertension in pregnancy is characterised by abnormalities in the vascular endothelium, with abnormal CECs and vWf that correlate with BPs. This may reflect dysfunctional processes that are counteracted with reparative attempts at restoring endothelial integrity.

The effects of exercise stress testing, diurnal variation and temporal decline on circulating progenitor cells.

Endothelial damage/dysfunction is involved in numerous cardiovascular disease processes. Given that the mature endothelial cells have limited capacity for self regeneration, circulating progenitor cells (CPCs) may modulate the balance between vascular damage and regeneration. The three aims of the present study were 1) to define the influence of exercise treadmill testing (ETT) on peripheral CPC levels; 2) to assess the diurnal variation of CPC counts; and 3) to investigate the rate of temporal decline in CPCs once ex vivo . The dynamics of CPC count changes following an ETT were assessed on consecutive 20 patients referred to our 'rapid-access' chest pain clinic (70% male, age 69.9 +/- 7.8) with venous blood samples taken pre-exercise, immediately post-exercise and at 30 minutes post-exercise. Diurnal variation in CPCs was assessed in 13 stable in-hospital patients (46% male, age 69.1 +/- 7.5 years) with blood samples were taken five times every 6 hours. To investigate the temporal decline, blood samples from 12 patients (58.3% male, age 69.9 +/- 7.9 years) were reprocessed for CPC counts at 4 hours and at 24 hours after sample collection. Plasma levels of von Willebrand factor (vWf) and soluble E-selectin (sE-selectin) were assessed by ELISA. CPCs were enumerated with flow cytometry as CD34+, CD133+, CD45dim events. Exercise led to significant increases in vWF and sE-selectin levels, but no significant influence on CPC counts were observed. Baseline CPC numbers demonstrated a negative correlation with vWf (r=-0.551, p=0.012) and sE-selectin levels (r=-0.494, p=0.027). CPC counts showed a significant diurnal variation, being significantly higher at 12 a.m. compared to 12 p.m. (p=0.046) and 6 p.m. (p=0.023). A 4 hour delay in sample preparation did not affect CPCs counts, but there was a significant decline in CPC recovery when sample processing was delayed by 24 hours (p<0.05). Routine exercise stress testing does not significantly affect CPC counts. Peripheral CPC levels showed a significant diurnal variation. Delays in sample preparation for CPC counts should be avoided as they may influence the accuracy of the test by resulting in a significant decline in CPC recovery. Thus, various factors may affect accuracy of CPC enumeration that may limit their role as a reliable clinical marker and biomarker of endothelial damage.

Hypertension in pregnancy: pathophysiology and management strategies.

Hypertension is the most common medical condition encountered in and complicating pregnancy, with significant implications on maternal and perinatal morbidity and mortality. It is also one of the areas of clinical practice that has been studied extensively, yet less well understood. The hypertensive disorders of pregnancy are a spectrum of conditions that are classified into 4 categories based upon recommendations of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. This article provides an overview of the pathophysiology and current pharmacologic management of hypertension in pregnancy.

Blood pressure control and prevention of stroke.

Hypertension is an important risk factor for stroke. The latter results in disability and premature death and represents a major public health problem. Various studies have established a strong relationship between increasing blood pressure and stroke risk, as well as clear evidence of a reduction in the incidence of strokes in response to even relatively small decreases in blood pressures. In this review, the pharmacological treatment of hypertension and the benefit on stroke prevention is outlined.

The financial cost of optimising blood pressure control.

We have investigated the financial costs of attempts to optimise blood pressure control in patients referred to our blood pressure clinic. At first referral, the average blood pressure in the 262 patients studied were 167/97 mmHg and the monthly costs of the antihypertensive drugs was 23.44 pounds. After 1 year of clinic attendance, the blood pressure was reduced to 149/87 mmHg, and the average drug costs had risen to 30.68 pounds. For drug expenditure alone, the cost of reducing systolic blood pressure by 1 mmHg was 0.36p pounds (Euro 0.55, USD 0.55) and for diastolic blood pressure the cost-was 0.72p pounds (Euro 1.12, USD 1.13).