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.

Do we need more long-term outcome trials for the treatment of hypertension?

The epidemiology of arterial hypertension and its treatment has been underlined by a huge research literature. Consistently raised arterial blood pressure in a clinic or home setting is a simple clinical observation that marks a predilection to a variety of fatal and non-fatal vascular disease events. Over the past 50 years tolerable, safe and effective primary and secondary medicines to offset a substantial amount of the associated morbidity and mortality risk of elevated blood pressure have emerged. Due to the nature of the population-relative risk and low absolute risk of this phenomenon it has often taken very large numbers of patients recruited from multiple centres in several countries and huge financial investment to define these profiles. Few national clinical research funds have invested in this process and it has often been left to a relatively small group of investigators to work closely with the commercial producers of new medicines to complete the essential outcome trials on which much of contemporary cardiovascular medical practice is based. Currently there are few, if any, significant new drug entities relevant to raised blood pressure under development. Most of the underlying clinical management principles and associations are clear. Achieved blood pressure, through patient adherence and variable prescriber practice, defines outcomes for individuals. The theoretical likelihood of a major step forward in the understanding of raised arterial blood pressure or a preferred means for population management is low. Moreover, with few new drug entities, investment in major outcome trials is unlikely to be proposed and the target for new trials is perhaps less apparent. While there can be no doubt that few areas in recent medical practice have benefited more from such huge achievements in underlining treatment, is it time to move on from the cardiovascular mega trial in hypertension?

Left ventricular hypertrophy by Sokolow-Lyon voltage criterion predicts mortality in overweight hypertensive subjects.

In view of the low sensitivity of Sokolow-Lyon voltage criteria in the assessment of electrocardiographic left ventricular hypertrophy (ECG LVH) in overweight subjects, we determined its clinical utility in 1840 lean and 3555 overweight subjects with hypertension. They were followed prospectively over an average of 11 years by the Department of Health and Social Security Hypertension Care Computer Project. LVH was determined at baseline using the Sokolow-Lyon criterion that is, the amplitude voltage SV1+(max RV5 or RV6) > or =3.5 mV. Overweight status was defined as body mass index (BMI) > or =25 kg m(-2). Prevalence of ECG LVH was 16% in lean and 12% in overweight women, 35 and 20% in lean and overweight men. For each 0.1 mV increase in ECG voltage as a continuous variable, the age and sex adjusted risk of stroke, coronary heart disease and cardiovascular disease (CVD) mortality increased significantly by 3.0, 1.5 and 1.8% in overweight subjects and by 2.8, 1.8 and 2.4% in lean subjects. After additional adjustments for smoking, blood glucose and serum cholesterol concentration in a subgroup of 654 lean and 1281 overweight subjects with complete information on these variables, an increasing voltage still significantly predicted stroke and CVD mortality in overweight subjects. The excess high risk of dying was evident especially in women with LVH in the highest BMI quartiles. When ECG detects LVH in overweight subjects, it is a good predictor of mortality despite the lower sensitivity in this group.

Ethnic differences in cancer incidence and mortality: the Birmingham Factory Screening Project.

BACKGROUND: There is little information on ethnic differences in the incidence of cancer and cancer mortality among adults in the UK, particularly concerning Afro-Caribbean people. AIM: To examine differences in the incidence of malignant cancer and cancer mortality rates among White European, Afro-Caribbean, and South-Asian people, and to examine baseline demographic predictors of cancer mortality. DESIGN: Longitudinal cohort study. METHODS: We compared ethnic differences in the incidence of malignant cancer and cancer mortality over a mean (SD) follow-up of 19.9 (4.8) years, in relation to baseline demographic characteristics and blood pressure variables, in the 2713 participants (2090 White European men and women, 428 Afro-Caribbean men and women, and 195 South Asian men) enrolled in the Birmingham Factory Screening Project whose survival status on 31 December 2003 was known. RESULTS: White European women had a significantly higher incidence of cancer compared to Afro-Caribbean women (p=0.019). In addition, South Asian men had a significantly lower incidence of cancer compared to White European men (p<0.0001) and Afro-Caribbean men (p=0.048). The incidence of cancer was similar in White European and Afro-Caribbean men (p=1.00). Overall incidence densities of cancer and death from cancer were 0.6% and 0.3% per 100 person-years of observation, respectively. Age, ethnicity, and smoking status were independent predictors of both cancer incidence and cancer mortality. DISCUSSION: The incidence of, and death from, cancer are both lower in minority ethnic groups in the UK, than in their White European counterparts.

Left ventricular hypertrophy determined by Sokolow-Lyon criteria: a different predictor in women than in men?

The clinical usefulness of the Sokolow-Lyon voltage criteria in the assessment of electrocardiographic left ventricular hypertrophy (ECG LVH) is addressed. We prospectively studied 3,338 women and 3,330 men referred with hypertension, with an average follow-up of 11.2 years. The voltage amplitude sum SV1+max (RV5 or RV6) was calculated and ECG LVH was defined as a sum >or=3.5 mV. We adjusted survival for age, treatment status before presentation and a previous myocardial infarction or cerebrovascular accident. The risk of stroke, coronary heart disease (CHD) and cardiovascular disease (CVD) mortality increased significantly for each quantitative 0.1 mV increase in baseline electrocardiogram (ECG) voltage, in women within the range of 1.6-3.9% and in men 1.4-3.0%. After further adjustments for race, body mass index, smoking and systolic blood pressure, increasing voltage independently predicted CVD mortality in both men and women. In women, both increasing voltage and the presence of left ventricular hypertrophy (LVH) were predictors of stroke mortality, whereas in men this risk was attenuated. In men, the adjusted association between increasing voltage and CHD mortality tended to be stronger than in women. The use of different thresholds for the two genders made little difference. For stroke and CHD mortality, the population attributable fractions associated with LVH were 15.2 and 5.4% in women and 12.8 and 8.5% in men, respectively. In conclusion, the greater the baseline ECG voltage sum, the greater the associated CVD mortality risk. Women tended to have a high risk of stroke mortality owing to LVH despite adjustments.

Abnormal angiopoietins 1&2, angiopoietin receptor Tie-2 and vascular endothelial growth factor levels in hypertension: relationship to target organ damage [a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)].

BACKGROUND: The increased risk of target organ damage (TOD) in hypertension may be related to a prothrombotic or hypercoagulable state, with abnormalities in platelet activation. Altered angiogenesis, possibly related to increased plasma vascular endothelial growth factor (VEGF) is also a feature of hypertension. We hypothesized a link between altered angiogenesis and TOD in hypertension. Accordingly, the angiogenic growth factors VEGF, angiopoietin 1 and 2 (Ang 1 & 2) and soluble angiopoietin receptor Tie-2 in plasma and in platelets were assessed in terms of the presence or absence of hypertensive TOD. METHODS: We studied 199 patients (75% men; mean age 68 years) with hypertension. Of these, 125 had evidence of hypertensive TOD (stroke, previous myocardial infarction, angina, left ventricular hypertrophy and mild renal failure). Patients were compared with 74 healthy normotensive controls (69% men; mean age 68 years). Plasma VEGF, Ang 1 & 2 and Tie-2, and total platelet levels of VEGF and Ang-1 (obtained by lysing a known number of platelets with 0.5% Tween) were measured by an enzyme-linked immunosorbent assay. RESULTS: Hypertensive patients had higher levels of plasma VEGF, Ang-1, Ang-2, Tie-2 and platelet VEGF (all P

Factors predicting the development of metabolic syndrome and type II diabetes against a background of hypertension.

BACKGROUND: The metabolic syndrome (MetS), predicting coronary heart disease (CHD), is a compound of risk factors including diabetes, obesity and hypertension. The relationship between the development of MetS, diabetes and CHD in patients with established hypertension is unclear. We hypothesized that patients with hypertension developing MetS are at increased risk of type II diabetes and CHD compared with patients who do not develop MetS. MATERIALS AND METHODS: We prospectively studied 284 patients (100 with existing/established MetS) with hypertension but without diabetes and CHD over 4 years. MetS and diabetes were diagnosed by the modified NCEP and ADA criteria, and CHD risk by the Framingham risk equation; all patients had annual fasting blood sampling. RESULTS: Over 4 years of follow up, 75 of the 184 patients (41%) initially free of MetS at baseline subsequently fulfilled the criteria for MetS. These patients (i.e. 'developing MetS') had higher baseline BMI, triglycerides and lower HDL cholesterol, with a higher calculated CHD risk (all P

Echocardiographic changes in patients with malignant phase hypertension: the West Birmingham Malignant Hypertension Register.

In order to study the echocardiographic abnormalities in consecutive patients with malignant phase hypertension (MHT), we reviewed echocardiograms of 31 patients (23 male; mean age 52+/-14 years) with MHT who were admitted to our unit. Trans-thoracic echocardiography was carried out in all patients, and echocardiographic measurements were compared with those of 39 patients (30 male; mean age 54+/-10 years) with controlled nonmalignant essential hypertension, and 32 (19 male; mean age 51+/-10 years) healthy normotensive volunteers. Patients with MHT had a significantly higher mean systolic and diastolic blood pressure (P<0.001) compared to the other two groups. MHT patients had significantly greater mean left atrial dimensions (P=0.002), as well as aortic root dimensions (P=0.01) and left ventricular (LV) dimensions (with the exception of the diastolic internal diameter) (P<0.001). MHT patients also had a mean larger LV mass and LV mass index (both P<0.001) when compared to the other two groups. The mean ejection fraction was also lower in the MHT group (P<0.001). In conclusion, patients with MHT have significant cardiac hypertrophy, in association with systolic dysfunction and dilated left atria, irrespective of the duration of known hypertension. These abnormalities may predispose MHT patients to cardiovascular complications including heart failure and cardiac arrhythmias, such as atrial fibrillation.

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).

Ethnic differences in left ventricular size and the prevalence of left ventricular hypertrophy among hypertensive patients vary with electrocardiographic criteria.

The objective of this study was to investigate differences in electrocardiographic (ECG) parameters and the prevalence of left ventricular hypertrophy (LVH) by various ECG criteria between different ethnic groups in west Birmingham, United Kingdom. In all, 380 consecutive patients, mean age 63 (7.8) years, 75 (20%) female patients assessed for inclusion in hypertension trials in a city centre teaching hospital were studied: 303 (80%) were Caucasian, 43 (11.4%) Afro-Caribbean and 32 (8.5%) South Asian. LVH was assessed using seven different criteria, with adjustment for age and body mass index (BMI). The performance of the various criteria were compared between the three ethnic groups. There were significant differences in the R-wave voltage in lead aVL, the Sokolow-Lyon voltage and in criteria based on limb lead voltages alone between the three ethnic groups. Highest ECG voltages were seen in Afro-Caribbeans, and this translated into a significantly higher prevalence of LVH when assessed by the R-wave in aVL and the Sokolow-Lyon criteria. There were no significant differences between Caucasians and South Asians. These differences were abolished after adjustment for age and BMI. There was no difference in the Cornell voltage or its derivatives in men between the three ethnic groups. In conclusion, apparent differences in electrocardiographic voltage and the prevalence of LVH between ethnic groups are dependent upon the criteria chosen and may simply be secondary to differences in BMI. Unlike Afro-Caribbean patients, South Asians do not demonstrate significant differences in ECG voltage compared with Caucasians.

Strategies for improvement of awareness, treatment and control of hypertension: results of a panel discussion.

High blood pressure (BP) is a major risk factor for coronary heart disease, heart failure, stroke, chronic kidney disease, end stage renal disease, and a variety of other clinically important outcomes. Results from the surveys described in this issue and elsewhere underscore a common finding that hypertension is both highly prevalent and insufficiently treated and controlled. Recognizing the differences in sampling and survey measurement techniques, the reported prevalence of hypertension (SBP/DBP >/=140/90 mmHg or treatment with antihypertensive medication) in adults exceeded 25% in all of the surveys reported in this issue. In Latvia, the prevalence of hypertension for 25-64-year-old adults in the general population was 46.1%. Control of hypertension with medication to an SBP/DBP <140/90 mmHg in the general population ranged from as low as 12% to a high of only 29%. Data from other parts of the world provide an equally distressing picture of what is (not) being accomplished in treatment and control of hypertension at the level of the general population. These data provide testimony to an urgent need for greater attention to the treatment and control of hypertension in populations around the world. This was the basis for a panel discussion at the International Society of Hypertension satellite conference The Epidemiology of Hypertension-Regional Differences in Treatment and Control. Panel participants included Drs P Whelton, S Sonkodi, DG Beevers, JG Fodor, H Elliot, R Cifkova, A Nissinen, A Javor, and there was active participation of other symposium attendees. The following summarizes key elements of the discussion and recommendations of the panel.

Epidemiological, pathophysiological and clinical significance of systolic, diastolic and pulse pressure.

Long-term population surveys and studies of untreated hypertensive patients both strongly suggest that over the age of about 45, the height of the systolic blood pressure is a better predictor of cardiovascular outcome than the diastolic pressure. Research into echocardiographic left ventricular size, endothelial function and thromborheology also back up this supposition. In clinical practice, the treatment of isolated systolic hypertension has been shown to be very worthwhile. There remains some uncertainty as to the relative significance of diastolic blood pressure when it is frankly high, as in severe systo-diastolic hypertension. However some clinicians and epidemiologists have questioned whether diastolic pressure is still worth measuring, given the overwhelming importance of the height of the systolic blood pressure at predicting outcome.

Platelet and haemorheological markers in 'high risk' hypertensives are improved by tighter blood pressure control and cardiovascular risk management: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

OBJECTIVE: To investigate the impact of intensified cardiovascular risk management on soluble markers of platelet, endothelial and rheological function in a population of middle-aged hypertensive patients at high risk of cardiovascular complications. DESIGN: Prospective follow-up study. SUBJECTS AND METHODS: A total of 159 hypertensive patients [138 male, mean age 64 (+/-8) years] and 80 healthy controls were studied. Plasma levels of soluble P-selectin (sP-sel, a marker of platelet function), von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and rheological indices [fibrinogen (Fib), plasma viscosity (PV), haematocrit (HCT), white blood count (WBC) and platelet count] were measured at baseline and again (in the patients) after 6 months' treatment. RESULTS: As expected, 6 months of intensified cardiovascular risk management resulted in a significant fall in mean blood pressure (BP) and total cholesterol. It also resulted in reduced haematocrit, vWF, sP-sel, WBC and PV levels (all P < 0.001), but not plasma fibrinogen. There were no correlations between the fall in BP and the improvement in any of the research indices. CONCLUSIONS: Intensified cardiovascular risk management results in significant improvements in indices of endothelial, platelet and rheological function in a population of hypertensives at high risk of cardiovascular events. These improvements appear to be independent of the degree of change in BP. Given the fundamental role of interactions between the endothelium and circulating blood components in the pathogenesis of hypertensive complications this may be of importance in preventing adverse cardiovascular outcomes.