For Debate: The 2023 European Society of Hypertension guidelines - cause for concern.

Originally, the beta-blockers were equally ranked alongside the other antihypertensive drug classes. Things changed when two major long-term randomized controlled trials, ASCOT-BPLA and LIFE showed that the patients receiving the beta-blockers based regimes suffered 25-30% more strokes than those receiving a calcium channel blocker based regime or an angiotensin receptor blocker based regime. The inferiority of the beta-blockers at stroke prevention was not due to differences in blood pressure control during the follow-up period in both trials. The 2023 European Society of Hypertension (ESH) guidelines still argue in favour of beta-blockers that their clinical inferiority was simply to lesser blood pressure reduction rather than class effect. The analysis argues that the return of beta-blockers as a first-line option for the management of uncomplicated hypertension by the ESH is a cause for concern and should be reconsidered.

A randomized trial of ambulatory blood pressure monitoring versus clinical blood pressure measurement in the management of hypertension in pregnancy. A feasibility study.

To assess the feasibility of a prospective randomised trial of ambulatory blood pressure monitoring (ABPM) versus clinic blood pressure (CBP) readings for managing pregnancy hypertension. The primary outcome measure was admission to hospital. The secondary measures were number of antenatal attendances, use of anti-hypertensive drugs and duration of hospital stay. In general, there were no statistical differences between the two groups including the primary outcome, the rate of hospital admission p=0.76. 89% of participants would undergo ABPM in future pregnancies. A randomised trial of ABPM in pregnancy using this methodology is feasible and acceptable to pregnant women.

Predictors of 5-year outcomes in malignant phase hypertension: the West Birmingham Malignant Hypertension Registry.

OBJECTIVE: Malignant hypertension represents a high-risk condition and there are scarce data on current clinical patterns of this condition. The aim of the study is to identify the clinical and demographic factors associated with poor outcome. METHODS: The data collected from 1958 to May 2016 included a total of 351 patients whose 5-year survival status was known: 221 white Caucasians (63%, age 51 ±â€Š13 years, 64% male), 83 African-Caribbeans (24%, 45 ±â€Š11 years, 61% male), and 47 South Asians (13%, 42 ±â€Š11 years, 74% male). RESULTS: During the 5-year follow-up 119 (34%) patients suffered a primary outcome, defined as the composite endpoint of death or dialysis. The 5-year mortality ranged from 76% in patients diagnosed before 1967 to 7% in patients diagnosed between 1997 and 2006. The independent predictors of outcome were advanced age (vs. a reference group of < 40-year-old; P = 0.01 for age at presentation 51-60 years, P < 0.001 for age > 60 years), prior use of antihypertensive medications (P = 0.002), higher serum creatinine (P = 0.006), and proteinuria (P < 0.01). Also, white Caucasian (odds ratio12.02, 95% confidence interval 1.64-88.15, P = 0.01) and African-Caribbean (odds ratio 15.55, 95% confidence interval 2.06-117.29, P = 0.008) origins were associated with higher mortality vs. South Asians. The years of the diagnosis after 1977 were significantly associated with lower composite endpoint of death or dialysis, all P < 0.01. CONCLUSION: There has been a major improvement in 5-year survival in patients with malignant hypertension over recent decades. Abnormal renal function at presentation still predicts worse outcome. South Asian ethnicity is also associated with better outcome, although mechanisms involved are yet to be established.

Does obesity influence target organ damage and outcomes in patients with malignant phase hypertension? The West Birmingham Malignant Hypertension Project.

Several studies have suggested that hypertension has a stronger detrimental impact on cardiovascular outcome in lean than in obese persons, but neutral or opposite results have also been reported. We investigated the impact of baseline body mass index (BMI) at presentation with the most severe form of hypertension, that is, malignant phase hypertension (MPH) on the primary outcome of 'death or dialysis' in these patients. A total of 184 patients (overall mean (s.d.) age 48 (13) years; 61% male; 62% White-European; 20% African-Caribbean, 18% South-Asian) from the West Birmingham MPH Register were included. The patients were grouped according to their BMI (underweight, normal weight, overweight and obese groups). Ninety-three primary outcomes occurred during a median (interquartile range) follow-up of 10.7 (5.8-18.6) years. No significant baseline differences in age or ethnicity were seen between the study groups. Overweight and obese patients included a larger proportion of females, but less smokers than those underweight or of normal weight. There was no inter-group difference in retinopathy (P=0.25), proteinuria (P=0.08), haematuria (P=0.56) and left ventricular hypertrophy (P=0.14). In univariate analyses, BMI was predictive of death or dialysis (0.95 (0.90-1.00), P=0.046) but multivariate analyses showed that only baseline age (odds ratio (95% confidence intervals) 1.06 (1.03-1.09), P<0.001), smoking (2.89 (1.40-5.92), P=0.004), creatinine level (1.01 (1.01-1.02), P=0.001) and estimated glomerular filtration rates (0.99 (0.93-1.00), P=0.047) were independently associated with death or dialysis. BMI was not an independent predictor of adverse outcomes in MPH patients. Age, smoking status, creatinine levels and estimated glomerular filtration rates at diagnosis of MPH were independent predictors for death or dialysis in this high-risk population of hypertensive patients.

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.

A comprehensive assessment of cardiac structure and function in patients with treated malignant phase hypertension: the West Birmingham Malignant Hypertension project.

BACKGROUND: Previous studies have confirmed that cardiac structural and functional abnormalities exist in patients with malignant hypertension (MHT). The effect of long-term blood pressure control in MHT patients on cardiac structure and function is still unknown. METHODS: We performed detailed left ventricle (LV) assessment using two-dimensional (2DE) and three-dimensional (3DE) echocardiography, and tissue Doppler imaging (TDI) in patients with previous MHT (but now in stable phase) who were compared with patients with treated 'high risk' hypertension (HHT, but non-MHT) and healthy controls (HC). Vasodilator stress myocardial contrast echocardiography (in addition to wall motion analysis) was used to exclude significant coronary artery disease, as part of our comprehensive echocardiographic assessment. Septal and posterior wall thickness, LV mass index, LV volumes and ejection fraction, mitral valve inflow indices (E, A) mitral annular velocity (S, E') and left atrial volume index (LAVI), were calculated using 2DE, 3DE, and TDI. MHT patients had good blood pressure control for an average of 144months. RESULTS: A total of 95 subjects (MHT=15; HHT and HC=40 each) were studied. Both posterior and septal wall thickness were significantly higher in the MHT and hypertensive groups compared to normal controls with no difference between MHT and HHT. No significant difference in LV ejection fraction was found between the 3 groups. Increased LAVI (p<0.05 MHT vs. HC and HHT vs. HC), reduced 'S' velocity on TDI (p=0.05 MHT vs. HC and vs.HHT, p<0.001 HHT vs. HC) and higher E/E' (p=0.029 HHT vs. HC) and lower E/A ratio (p=0.001 MHT vs. HC, p<0.001 HHT vs. HC) values were detected in the two hypertensive groups. CONCLUSION: Despite long-term good blood pressure control, MHT patients have persistent structural and functional changes in LV function on echocardiography, comparable to that seen in HHT.

Lack of impact of pulse pressure on outcomes in patients with malignant phase hypertension: the West Birmingham Malignant Hypertension study.

OBJECTIVE: To investigate the impact of pulse pressure at presentation on the primary outcome (death or dialysis) in patients with malignant phase hypertension (MPH). METHODS: Three hundred and sixty-five patients [overall mean (SD) age 48 (13) years; 66% male; 63% white European; 23% African-Caribbean, 14% south Asian] from the West Birmingham MPH study were included. Baseline pulse pressure was divided into quartiles. Two hundred and forty-two primary outcomes (death or dialysis) occurred during a median (interquartile range) follow-up of 7 (1.5-14.8) years. RESULTS: Significantly higher pulse pressure was evident among older patients and white Europeans. Baseline BMI (P = 0.49), retinopathy (P = 0.56), proteinuria (P = 0.61), haematuria (P = 0.56) and left ventricular hypertrophy (P = 0.43) were not related to pulse pressure. Multivariate analyses found that baseline age [hazard ratio (95% confidence intervals] [1.05 (1.04-1.06); P < 0.0001], smoking [1.60 (1.16-2.21); P = 0.004], proteinuria [1.33 (1.10-1.61); P = 0.003] and creatinine level [1.002 (1.001-1.002); P < 0.0001] were independent predictors of the primary outcome of 'death or dialysis'. A multivariate analysis also revealed that independent predictors of future dialysis alone were as follows: baseline age [0.92 (0.89-0.95); P < 0.001) and haematuria [2.74 (1.17-6.42); P = 0.02), with a trend seen for baseline creatinine levels [1.001 (1.000-1.002); P = 0.052)]. Pulse pressure at baseline did not predict death or dialysis. CONCLUSION: Age, smoking status and severity of renal failure at presentation with MPH (represented by proteinuria and creatinine levels) are independent predictors of the risk of death or dialysis. Pulse pressure at presentation does not predict death or dialysis in patients with MPH. Careful monitoring of renal functioning and effective management of blood pressure is mandatory in patients with MPH to prevent/slow future complications.

Angiogenin and hemoxygenase in pregnancy: influence of hypertension.

The pathophysiology of hypertension and preeclampsia involves angiogenesis and endothelial damage/dysfunction, as shown by abnormal growth factors (vascular endothelial growth factor [VEGF], and its receptor sFlt-1) and von Willebrand factor (vWf) in the plasma. Angiogenin and hemoxygenase are abnormal in hypertension and angiogenesis but data on pregnancy are scant. We hypothesized altered angiogenin and hemoxygenase in 38 hypertensive pregnant women (HTPW) compared to 38 normotensive pregnant women (NTPW) and 50 nonpregnant controls (NonPCs). Plasma markers were measured by enzyme-linked immunosorbent assay (ELISA). Hypertensive pregnant women had lower VEGF than NonPCs (P < .01), vWf was raised in both pregnant groups (P < .01), but sFlt-1 was no different. Both angiogenin and hemoxygenase were lower in NTPW compared to NonPCs (both p<0.02). In both pregnancy groups, angiogenin correlated with vWf (r > .33, P < .05), but in NonPCs this was not significant (r = .13, P = .367). These changes may reflect differences in endothelial cell physiology and pathology in the hypertension in pregnancy.

Soluble Fas and Fas ligand in pregnancy: influence of hypertension.

The pathophysiology of pregnancy-induced hypertension and preeclampsia may involve abnormalities in placentation and the Fas/Fas ligand system. Hypothesizing abnormal plasma Fas and Fas ligand in pregnancy-induced hypertension, we recruited 20 hypertensive pregnant women at mean week 15 and 29 at week 30: 18 were studied at both time points. Control groups were 20 normotensive pregnant women at week 20, 29 women at week 27, and 50 nonpregnant women. sFas and sFas ligand (sFasL) were measured by enzyme-linked immunosorbent assay (ELISA). The hypertensive women had lower sFasL at both stages of their pregnancy (P < .05). There were no differences in sFas. In 18 hypertensive pregnant women, sFasL fell from week 15 to week 29 (P < .03). We conclude that sFas and sFasL is unchanged in normal pregnancy. Hypertension in pregnancy is characterized by low sFasL, and levels fall from weeks 15 to 29. This may reflect differences in placentation in the differing physiological and pathological states.

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?

The bio-tribological characteristics of synthetic tissue grafts.

The use of synthetic connective tissue grafts became popular in the mid-1980s, particularly for anterior cruciate ligament reconstruction; however, this trend was soon changed given the high failure rate due to abrasive wear. More than 20 years later, a vast range of grafts are available to the orthopaedic surgeon for augmenting connective tissue following rupture or tissue loss. While the biomechanical properties of these synthetic grafts become ever closer to the natural tissue, there have been no reports of their bio-tribological (i.e. bio-friction) characteristics. In this study, the bio-tribological performance of three clinically available synthetic tissue grafts, and natural tendon, was investigated. It was established that the natural tissue exhibits fluid-film lubrication characteristics and hence is highly efficient when sliding against opposing tissues. Conversely, all the synthetic tissues demonstrated boundary or mixed lubrication regimes, resulting in surface-surface contact, which will subsequently cause third body wear. The tribological performance of the synthetic tissue, however, appeared to be dependent on the macroscopic structure. This study indicates that there is a need for synthetic tissue designs to have improved frictional characteristics or to use a scaffold structure that encourages tissue in-growth. Such a development would optimize the bio-tribological properties of the synthetic tissue and thereby maximize longevity.

Persistent macrovascular and microvascular dysfunction in patients with malignant hypertension.

Endothelial dysfunction is characteristic of patients with essential hypertension, but only limited data are available on different aspects of endothelial function in patients with malignant-phase hypertension. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial damage/dysfunction in patients with previous malignant hypertension (but now in stable phase), who were compared with patients with treated "high-risk" hypertension (hypertension) and healthy controls. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), microvascular (forearm) response to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, circulating endothelial and endothelial progenitor cells in 15 patients with malignant hypertension, 40 matched patients with hypertension, and 40 healthy controls. Patients with malignant hypertension had impaired endothelial-dependant response to acetylcholine (P<0.001, but not to sodium nitroprusside) compared with hypertension and impaired reaction to both stimuli compared with healthy subjects (P<0.001). Patients with malignant hypertension had increased circulating endothelial cells (P=0.001), endothelial progenitors (P=0.008), and stiffness (P=0.003). Both hypertensive groups had impaired response to hyperemia and glyceryl trinitrate when compared with healthy controls (P<0.05). Both hypertensive groups had similar myocardial perfusion, which was significantly lower than in healthy controls. There were no significant differences in hyperemia and endothelium-independent stimuli between the 2 hypertensive groups. In conclusion, despite fairly well-controlled blood pressure, malignant hypertension patients had more pronounced abnormalities of macrovascular and microvascular function (which seem to be both endothelium dependent and endothelium independent) compared with patients with hypertension and healthy controls.

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.

Are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers safe in pregnancy: a report of ninety-one pregnancies.

BACKGROUND: Both angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor antagonists (ARBs) have been reported to be associated with an excess of congenital abnormalities in infants born to women who took these drugs in pregnancy. METHODS: To investigate this possible association further, we have examined the outcome in 91 pregnancies in which the mother took either an ACE-I (n = 71) or an ARB (n = 20) in early pregnancy. We also examined the United Kingdom adverse drug reaction reporting system to assess the total number of reported associations of ACE-I or ARB use in pregnancy and congenital anomalies reported. RESULTS: Eight (8.8%) of the pregnancies led to an infant with a developmental anomaly, but all save one of these (craniosynostosis with tower skull) anomalies were considered to be relatively minor. The adverse drug reaction reporting system revealed a total of 43 reported defects in women taking an ACE-I and 12 in women taking an ARB. CONCLUSION: We have not found any convincing excess of congenital anomalies in women taking angiotensin-blocking drugs in early pregnancy. However, this does not exclude the possibility that ACE-I or ARB use in pregnancy might lead to adverse obstetrical outcomes. Until this matter is settled, we support recommendations that these drugs should not be used in pregnancy or in women who are likely to become pregnant.

Improving survival of malignant hypertension patients over 40 years.

BACKGROUND: To examine changing demography and survival of patients with malignant phase hypertension (MHT) over 40 years. METHODS: Patients from our MHT registry whose survival status on 31 December 2006 was known were included, with analyses conducted based on decade of MHT diagnosis. RESULTS: Four-hundred and forty-six patients with MHT (overall mean (s.d.) age 48.2 (12.9), years; 65.5% male; 64.7% white-European; 20.4% African Caribbean, and 14.8% South-Asian) were included. No significant demographic differences at diagnosis were evident over the 40 years, with the exception of a significant increase (P = 0.001) in the proportion of MHT among ethnic minorities (South-Asian and Afro-Caribbeans). There were no significant differences in mean systolic blood pressure (SBP) at presentation but baseline diastolic BP (DBP) was significantly lower after 1976 (P < 0.0001). The total number of person-years of observation was 5,725.5 years, with a median (interquartile range (IQR)) length of follow-up of 103.8 (31.3-251.2) months. Overall 203 patients (55.6%) died, 125 (32.0%) within 5 years of diagnosis. There was a significant improvement in 5-year survival from 32.0% prior to 1977 to 91.0% for patients diagnosed between 1997 and 2006. SBP and DBP improved significantly during follow-up (P < 0.0001). Multivariate analyses revealed that age, decade of MHT diagnosis, baseline creatinine, and follow-up SBP were independent predictors of survival (all P < 0.0001). CONCLUSIONS: Demography and number of new cases of MHT have not changed dramatically over the past 40 years. Five-year post-MHT survival has improved significantly, possibly related to lower BP targets, tighter BP control, and availability of new classes of antihypertensive drugs.

Hypertension in ethnic groups: epidemiological and clinical perspectives.

In the UK and other developed nations, hypertension and its vascular complications are more common in ethnically African and South-Asian communities compared with Europeans. While these conditions are less common in rural India and Africa, they present a rising problem in expanding cities in all developing countries. Hypertension is, therefore, mainly related to environmental and lifestyle factors rather than genetically determined racial differences. Studies in the USA and elsewhere show that the striking differences in the prevalence of hypertension between people of African and European origin are greatly reduced after adjustment for socio-economic status. One important and probably genuine racial difference between ethnic groups is the significantly suppressed activity of the renin-angiotensin-aldosterone system in African-origin hypertensive patients. As a consequence of this, they are rather more sensitive to a low-salt diet but significantly less sensitive to drugs that block the renin-angiotensin-aldosterone system (angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers) and beta-blockers. There is also evidence that renin suppression is common in Japanese and Chinese hypertensive patients as well, although no direct comparisons between these two groups with European-origin patients have been carried out. The management and control of hypertension is unsatisfactory in all ethnic groups and all nations. No one group needs particular targeting; all need better quality systematic care.