Risk factors associated with retinal vein occlusion.

AIMS: Retinal vein occlusion (RVO) is the most frequent retinal vascular disease after diabetic retinopathy in which arterial risk factors are much more relevant than venous factors. The objective was to evaluate the role of risk factors in the development of the first episode of RVO. SUBJECTS AND METHODS: One hundred patients with RVO [mean age 56 years, 42% females and mean body mass index (BMI) 27.5 kg/m(2)] were recruited consecutively from the outpatient clinic of a tertiary hospital in Valencia (Spain). All subjects underwent clinical assessment including anthropometric and blood pressure measurements and laboratory test including homocysteine, antiphospholipid antibodies (aPLAs) and thrombophilia studies. In half of the subjects, a carotid ultrasonography was performed. Three control populations matched by age, sex and BMI from different population-based studies were used to compare the levels and prevalence of arterial risk factors. One cohort of young patients with venous thromboembolic disease was used to compare the venous risk factors. RESULTS: Blood pressure levels and the prevalence of hypertension were significantly higher in the RVO population when compared with those for the general populations. There was also a large proportion of undiagnosed hypertension within the RVO group. Moreover, carotid evaluation revealed that a large proportion of patients with RVO had evidence of subclinical organ damage. In addition, homocysteine levels and prevalence of aPLAs were similar to the results obtained in our cohort of venous thromboembolic disease. CONCLUSIONS: The results indicate that hypertension is the key factor in the development of RVO, and that RVO can be the first manifestation of an undiagnosed hypertension. Furthermore, the majority of these patients had evidence of atherosclerotic disease. Among the venous factors, a thrombophilia study does not seem to be useful and only the prevalence of hyperhomocysteinaemia and aPLAs is higher than in the general population.

[2022 Practice guidelines for the management of arterial hypertension of the Spanish Society of Hypertension]. / Guía práctica sobre el diagnóstico y tratamiento de la hipertensión arterial en España, 2022. Sociedad Española de Hipertensión - Liga Española para la Lucha contra la Hipertensión Arterial (SEH-LELHA).

Hypertension is the most important risk factor for global disease burden. Detection and management of hypertension are considered as key issues for individual and public health, as adequate control of blood pressure levels markedly reduces morbidity and mortality associated with hypertension. Aims of these practice guidelines for the management of arterial hypertension of the Spanish Society of Hypertension include offering simplified schemes for diagnosis and treatment for daily practice, and strategies for public health promotion. The Spanish Society of Hypertension assumes the 2018 European guidelines for management of arterial hypertension developed by the European Society of Cardiology and the European Society of Hypertension, although relevant aspects of the 2017 American College of Cardiology/American Heart Association guidelines and the 2020 International Society of Hypertension guidelines are also commented. Hypertension is defined as a persistent elevation in office systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg, and assessment of out-of-office blood pressure and global cardiovascular risk are considered of key importance for evaluation and management of hypertensive patients. The target for treated blood pressure should be < 130/80 for most patients. The treatment of hypertension involves lifestyle interventions and drug therapy. Most people with hypertension need more than one antihypertensive drug for adequate control, so initial therapy with two drugs, and single pill combinations are recommended for a wide majority of hypertensive patients.

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Xanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR). METHOD AND RESULTS: 40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity. CONCLUSIONS: Subjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.

[Temporal evolution of renal involvement in a necropsy study of HIV patients from the pre and HAART eras]. / Evolución temporal de la afectación renal en una serie necrópsica de pacientes VIH de las eras pre y TARGA.

BACKGROUND: The aim of the present study is to analyze the impact of high activity antiretroviral therapy (HAART) on renal lesions observed in autopsies of HIV patients. SUBJECTS AND METHODS: Clinical records and renal pathologic samples from 100 HIV patients, who had died between 1984 and 2006, were reviewed, 61 before 1997 (group I) and 39 after. 24 of them had not received HAART (group II) and 15 had (group III). Premortem clinical and analytical data were obtained. Renal samples were stained with hematoxilin-eosin, PAS, Masson trichrome and silver-methenamine. The final pathologic diagnosis was recorded along with the findings at glomerular, tubular and interstitial levels. HIVAN was defined as the presence of focal or segmental glomerulosclerosis with glomerular collapse and microcystic tubulo -interstitial lesions. RESULTS: The main causes of death were infections 68%, tumours 14%, and others 18%, especially liver diseases. Renal failure was present in 42% at the time of death. A predominance of tubular lesions exists in the three study groups, followed by interstitial lesions and glomerular lesions. The main diagnoses were acute tubular necrosis (ATN) and septic nephritis. Four cases of HIVAN were found. When the subjects who received HAART treatment were compared with those who did not, a significantly higher percentage of interstitial lesions in the group with HAART was observed. There were also more cases of acute tubular necrosis but these differences were not statistically significant. CONCLUSIONS: Renal lesions were frequent in HIV patients independent of the presence or absence of HAART.

Prevalence of low HDL cholesterol, and relationship between serum HDL and cardiovascular disease in elderly Spanish population: the PREV-ICTUS study.

OBJECTIVE: To assess the prevalence of low serum high-density lipoprotein cholesterol (HDL-C) concentration and the relationship between HDL-C and established cardiovascular disease (CVD) in an elderly Mediterranean population. METHODS: Analysis of Prevención del Riesgo de Ictus, a population-based study on Spanish subjects aged > or = 60 years. Low HDL-C was defined following the European guidelines for cardiovascular prevention [men: < 40 mg/dl (< 1.0 mmol/l); women: < 46 mg/dl (< 1.2 mmol/l)]. The relationship between low HDL-C or HDL-C concentration (in quintiles) and CVD was assessed through multivariate models that included cardiovascular risk factors, statins and subclinical organ damage. RESULTS: On 6010 subjects (71.7 years, 53.5% women), low HDL-C was present in 17.5% [95% confidence interval (CI): 16.5-18.5] and was more frequent in women [20.4% (19.0-21.8) vs. 14.1% (12.8-15.4) in men p < 0.001] and in patients with diabetes, CVD or statin therapy. Low HDL-C was independently associated with CVD [adjusted odds ratio (OR): 1.46, 95% CI: 1.22-1.74, p < 0.001]. The prevalence of CVD was higher as HDL-C concentration was lower (chi-square trend < 0.001). Compared with the highest quintile [> 65 mg/dl (> 1.67 mmol/l)], adjusted OR for CVD were 1.39 (1.10-1.76), 1.41 (1.11-1.80), 1.49 (1.18-1.89) and 1.91 (1.52-2.39), respectively for those in the fourth [57-65 mg/dl (1.46-1.67 mmol/l)], third [51-56 mg/dl (1.31-1.45 mmol/l)], second [46-50 mg/dl (1.18-1.30 mmol/l)] and first [< 46 mg/dl (< 1.18 mmol/l)] quintiles of HDL-C. This association was seen in males and females. CONCLUSIONS: A total of 17.5% of this Spanish population aged > or = 60 years had low HDL-C. We found a strong, independent and inverse association between HDL-C concentrations and established CVD, even at ranges of HDL-C considered as normal.

Key Messages for a Frailty Prevention and Management Policy in Europe from the ADVANTAGE JOINT ACTION Consortium.

In the 2015 Ageing Report, the European Commission (EC) and the Economic Policy Committee stated that coping with the challenge posed by an ageing population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems. The concern for this situation motivated the EC, the Parliament and many of the Member States (MS) to co-fund, in the 2015 call of the Third European Health Programme of the European Union 2014-2020, the first Joint Action (JA) on the prevention of frailty. ADVANTAGE JA brings together 33 partners from 22 MSs for 3 years. It aims to build a common understanding on frailty to be used in the MSs by policy makers and other stakeholders involved in the management, both at individual and population level, of older people who are frail or at risk for developing frailty throughout the European Union (EU). It is a formidable challenge but also a great opportunity for concerted action resulting in fostering effective and successful policies in frailty prevention and management in the participating MS. The Consortium has 2 years of hard work ahead to contribute to the needed change for frailty related disability free Europe. The first practical step towards this aim was the preparation of a document: the State of the Art on Frailty Report to support an overview of evidence of what works and what does not work on frailty prevention and management. Subsequently, this will be reflected in the advice that the JA will give to policy makers at MS level. Overall, these messages intend to be an instrument of added value to advocate for policy driven decisions on frailty prevention and management in the JA participating MSs and subsequently towards a frailty related disability free older population in Europe. The aim of this paper is to describe ADVANTAGE JA general structure, approach and recommendations towards a European health and social policy which will support frailty prevention in the participating MS.

LDL particle size and composition and incident cardiovascular disease in a South-European population: The Hortega-Liposcale Follow-up Study.

BACKGROUND: The association of low-density lipoprotein (LDL) particle composition with cardiovascular risk has not been explored before. The aim was to evaluate the relationship between baseline LDL particle size and composition (proportions of large, medium and small LDL particles over their sum expressed as small-LDL %, medium-LDL % and large-LDL %) and incident cardiovascular disease in a population-based study. METHODS: Direct measurement of LDL particles was performed using a two-dimensional NMR-technique (Liposcale®). LDL cholesterol was assessed using both standard photometrical methods and the Liposcale® technique in a representative sample of 1162 adult men and women from Spain. RESULTS: The geometric mean of total LDL particle concentration in the study sample was 827.2 mg/dL (95% CI 814.7, 839.8). During a mean follow-up of 12.4 ±â€¯3.3 years, a total of 159 events occurred. Medium LDL particles were positively associated with all cardiovascular disease, coronary heart disease (CHD) and stroke after adjustment for traditional risk factors and treatment. Regarding LDL particle composition, the multivariable adjusted hazard ratios for CHD for a 5% increase in medium and small LDL % by a corresponding decrease of large LDL % were 1.93 (1.55, 2.39) and 1.41 (1.14, 1.74), respectively. CONCLUSIONS: Medium LDL particles were associated with incident cardiovascular disease. LDL particles showed the strongest association with cardiovascular events when the particle composition, rather than the total concentration, was investigated. A change in baseline composition of LDL particles from large to medium and small LDL particles was associated with an increased cardiovascular risk, especially for CHD.

[Spanish Society of Hypertension position statement on the 2017 ACC/AHA hypertension guidelines]. / Documento de la Sociedad Española de Hipertensión-Liga Española para la Lucha contra la Hipertensión Arterial (SEH-LELHA) sobre las guías ACC/AHA 2017 de hipertensión arterial.

The American College of Cardiology (ACC) and the American Heart Association (AHA) have recently published their guidelines for the prevention, detection, evaluation, and management of hypertension in adults. The most controversial issue is the classification threshold at 130/80mmHg, which will allow a large number of patients to be diagnosed as hypertensive who were previously considered normotensive. Blood pressure (BP) is considered normal (<120mmHg systolic and <80mmHg diastolic), elevated (120-129 and <80mmHg), stage 1 (130-139 or 80-89mmHg), and stage 2 (≥140 or ≥90mmHg). Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP-lowering medication. In management, cardiovascular risk would be determinant since those with grade 1 hypertension and an estimated 10-year risk of atherosclerotic cardiovascular disease ≥10%, and those with cardiovascular disease, chronic kidney disease and/or diabetes will require pharmacological treatment, the rest being susceptible to non-pharmacological treatment up to the 140/90mmHg threshold. These recommendations would allow patients with level 1 hypertension and high atherosclerotic cardiovascular disease to benefit from pharmacological therapies and all patients could also benefit from improved non-pharmacological therapies. However, this approach should be cautious because inadequate BP measurement and/or lack of systematic atherosclerotic cardiovascular disease calculation could lead to overestimation in diagnosing hypertension and to overtreatment. Guidelines are recommendations, not impositions, and the management of hypertension should be individualized, based on clinical decisions, preferences of the patients, and an adequate balance between benefits and risks.

Impact of the components of metabolic syndrome on oxidative stress and enzymatic antioxidant activity in essential hypertension.

The objective of the present study was to analyze the impact of metabolic syndrome (MS) and its individual components on oxidative stress (OX) and on the activity of antioxidant enzymes of patients with essential hypertension. One hundred and eighty-seven hypertensives, 127 (61.9%) of them having criteria for MS according to the International Diabetes Federation criteria and 30 healthy normotensive subjects were included. OX status was assessed by measuring glutathione oxidized/glutathione reduced and reactive oxygen species-induced byproducts of lipid peroxidation, malondialdehyde, and DNA damage, 8-oxo-dG genomic and mitochondrial. Antioxidant enzymatic activity of Cu/Zn extracellular-superoxide dismutase (SOD) and catalase (CAT) was measured in plasma and glutathione peroxidase 1 in hemolysed erythrocytes. In mononuclear cells, total-SOD activity, CAT and glutathione peroxidase 1, were assessed as well. The OX state in both blood and peripheral mononuclear cells observed in hypertensives were not enhanced by the addition of components of the so-called MS. Likewise, the reduction in the activity of antioxidant enzymes, both extracellular and cytoplasmic, was not affected by the presence of additional components of the MS. Neither the number of components nor the individual addition of each of them, low high-density lipoprotein, triglycerides, abdominal obesity or fasting glucose, further impact in the OX abnormalities observed in those with only hypertension in absence of other components. In conclusion, the present data indicates that contribution of MS components to the OX burden generated by high blood pressure is minimal.

Catastrophic antiphospholipid syndrome related to severe ovarian hyperstimulation.

Antiphospholipid syndrome (APS) is a cause of infertility and fetal loss. Ovarian stimulation can induce previously unknown APS. Ovarian hyperstimulation syndrome (OHS) is uncommon but potentially life-threatening, as well as catastrophic APS. A woman that simultaneously developed a severe OHS and a catastrophic APS is described in this paper. Both entities produced thrombotic cardiac and brain thrombosis. A peculiar mechanism of cardiac ischemia is also described. In spite of the life-threatening risk of this situation, the indication for preventive anti-aggregation and/or anticoagulation is not clear.

Multimorbidity and acute heart failure in internal medicine.

AIMS: To analyse the characteristics of hospitalized patients for AHF, with special attention to the clustering of morbidities. METHODS AND RESULTS: Clinical records of patients, admitted in Internal Medicine due to AHF, during three years, were reviewed. The characteristics of patients-episodes were registered and key indicators of performance. Multiple correspondence analysis (MCA) was used to assess the distribution of morbidities. LR models were used to study clinical variables related with death or readmission. The median age was 80y, predominantly women and with multiple morbidities. As it was expected, CVRF were the main associated comorbidities followed by respiratory diseases, CKD and chronic anaemia. In the MCA, all the CVRF clustered around the origin so they explained little of the total inertia. Male sex, young age, IHD, obesity and lung disease were more common in reduced EF whereas female, older age and thyroid disease were more common in preserved EF. The confidence ellipses for death in hospitalization or during the follow-up or for readmissions overlapped, so it was not possible to identify clusters of morbidities to predict outcomes. The main causes for AHF were infections, anaemia and RVR in AF. Nearly 16% died during the hospitalization whereas 25.6% died and 56.3% were re-hospitalized during the following year after the discharge. Previous or repeated admissions to the hospital were the best single predictors for death or readmission. CONCLUSIONS: Strategies to control infections, anaemia and AF, in the outpatient settings, might help to reduce the burden of AHF, although this remains to be proven.

Regulation of intracellular pH in the spontaneously hypertensive rat. Role of bicarbonate-dependent transporters.

Previous studies that have evaluated the Na(+)-H+ antiporter in cells from hypertensive subjects were generally performed under conditions in which HCO3-CO2, the physiological buffer system, was absent from the assay media. The objective of this study was to evaluate the activity of the Na(+)-H+ antiporter and that of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchangers in cells assayed in the presence of HCO3-CO2 in the media. Lymphocytes from 6- to 8-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats were obtained from the thymus gland and assayed immediately after isolation. The activity of the Na(+)-H+ antiporter after stimulation by cell acidification (pHi approximately 6.4) was similar in SHR and WKY rats (18.67 +/- 1.03 and 16.12 +/- 0.92 mmol H+/L per minute, respectively). Recovery from cell alkalinization was effected by an Na(+)-independent Cl(-)-HCO3- exchanger, with maximal activity at an alkaline pHi (approximately 7.7). The stimulated activity of this Na(+)-independent Cl(-)-HCO3- exchanger was also not different between SHR and WKY cells (2.65 +/- 0.25 and 2.55 +/- 0.32 mmol H+/L per minute, respectively). Acute chloride removal produced a rise in pHi that was Na(+)-dependent and sensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) but resistant to ethylisopropylamiloride (EIPA), reflecting the activity of an Na(+)-dependent Cl(-)-HCO3- exchanger. Unlike the Na(+)-H+ exchanger and the Na(+)-independent Cl(-)-HCO3- exchanger, which had their highest activities at extremes of pHi (low pHi, Na(+)-H+ exchanger, and high pHi, Na(+)-independent Cl(-)-HCO3- exchanger), the Na(+)-dependent Cl(-)-HCO3- exchanger had its maximal activity near steady-state pHi (approximately 7.1). No significant differences were found in the stimulated activity of this exchanger between cells from SHR and WKY rats (2.23 +/- 0.26 and 2.50 +/- 0.43 mmol H+/L per minute, respectively). The kinetic properties of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchanger, examined as a function of external Cl-, were also virtually identical in cells from SHR and WKY rats. We conclude that in lymphocytes from SHR and WKY rats, the activity of the two Cl(-)-HCO3- exchangers, like that of the Na(+)-H+ exchanger, is dependent on the prevailing pHi. The Na(+)-dependent Cl(-)-HCO3- exchanger has its highest activity near steady-state pHi, suggesting an important role in the cell defense against intracellular acidosis under physiological conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Current and birth weights exert independent influences on nocturnal pressure-natriuresis relationships in normotensive children.

The objective was to study the impact of birth weight on the relationship between ambulatory blood pressure and urinary sodium excretion in children and adolescents. The study included 134 healthy children (61 boys), all Caucasians, who were born at term after a normotensive pregnancy. For each subject, a 24-hour ambulatory blood pressure monitoring and a complete urine collection were simultaneously performed according to the protocols designed. Average ambulatory blood pressure (BP) and the urinary excretion rates for sodium, potassium, and creatinine were calculated separately for 24-hour, awake, and sleep periods defined by a mini-diary. The excretion rate of sodium during sleep time was positively correlated with ambulatory systolic BP; such a positive relationship was not found for waking hours. Consequently, the impact of birth weight on the relationship between blood pressure and the urinary sodium excretion rate was analyzed during sleeping hours. Stepwise multiple regression analysis shows that although current weight was the strongest predictor for the sodium excretion rate during sleep (P<.001), there was also an independent significant direct relationship for birth weight (P<.04) after controlling for age, sex, and the average of systolic BP during sleep. Adjusted for current weight, a significant difference in the regression slopes relating urinary sodium excretion rate and systolic BP during sleep exists between children in the lowest (<3.100 kg) and the highest tertiles (>3.500 kg) of birth weight (P<.02). Differences in sodium excretion rates, adjusted for current weight, between the two extreme tertiles of birth weight became significant at the highest systolic BP (P<.04). The children who had the lowest birth weight tended to excrete less sodium during sleep. The results of the present study show a blunted pressure natriuresis curve in children and adolescents with the lowest birth weight. Whether this abnormal renal sodium handling may be present as an initial or as an intermediate mechanism leading to higher BP values must be assessed in additional studies.

Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population.

The objective of this study was to analyze the influence of the polymorphisms G-6A of the angiotensinogen gene, insertion/deletion (I/D) of the angiotensin-converting enzyme, and C573T of the angiotensin II AT1 receptor gene on a healthy, middle-age population. A total of 370 (194 women) healthy normotensive Caucasian subjects, aged 25-50 yr old, were selected from the general population. A significant association was found between height and the C573T polymorphism in women (P < 0.001). After adjustment for age, this association remained significant (P < 0.002). Thus, the lowest height values were from subjects carrying TT genotype (CC, 1.627 +/- 0.008 m; CT, 1.595 +/- 0.006 m; TT, 1.586 +/- 0.010 m; P = 0.002). Likewise, the I/D polymorphism was associated with height (P = 0.002) in women. It remained significant after adjustment for age and the lowest height for the DD genotype (II, 1.629 +/- 0.011 m; ID, 1.603 +/- 0.006 m; DD, 1.591 +/- 0.007 m; P = 0.016). For both C573T and I/D polymorphisms, there was an allele dosage effect. Moreover, an additive and independent effect of the C573T polymorphism (P = 0.006) and the I/D polymorphism (P = 0.045) on height was observed. In contrast, no association with height was observed for the G-6A polymorphism. In conclusion, additive effects between polymorphisms of the renin-angiotensin system genes and height were observed in healthy women. These results should be studied by other groups in other populations and ethnic groups. Whether or not these associations need to be considered in the epidemiological studies analyzing the relationship between polymorphisms of the renin-angiotensin system genes and such height-influenced parameters as blood pressure merits further study.

Altered blood pressure during sleep in normotensive subjects with type I diabetes.

This study was designed to examine the circadian pattern of blood pressure in children and young adults with type I diabetes who were completely normotensive by standard criteria. Forty-five patients and the same number of age- and sex-matched control subjects were studied. In diabetic children of 10-14 years of age, the nocturnal fall in systolic and diastolic blood pressures was intact. In diabetics of 15-20 years of age, the fall in systolic blood pressure was blunted; in diabetics of 21-37 years of age, the fall in both systolic and diastolic blood pressures during sleep was blunted. When data from all diabetic subjects were pooled and analyzed in a multiple linear regression model, mean blood pressure during sleep correlated best with urinary albumin excretion (r = 0.60). On the basis of this finding, we subdivided our patients into two groups: a microalbuminuric group (urinary albumin excretion > 30 mg per 24 hours; mean, 160.3 +/- 29.7; n = 11) and a normoalbuminuric group (urinary albumin excretion < 30 mg per 24 hours; mean, 6.6 +/- 6.5; n = 34). Both systolic and diastolic blood pressures during sleep were higher in microalbuminuric (121.1 +/- 3.3 and 69.3 +/- 2.5 mm Hg, respectively) than in normoalbuminuric diabetics (114.2 +/- 1.8 and 60.1 +/- 1.2 mm Hg, p < 0.05) or control subjects (113.3 +/- 1.2 and 60.1 +/- 1.2 mm Hg, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: a prospective study.

The objective of this study was to establish whether ambulatory blood pressure offers a better estimate of cardiovascular risk than does its clinical blood pressure counterpart in refractory hypertension. This prospective study assessed the incidence of cardiovascular events over time during an average follow-up of 49 months (range, 6 to 96). Patients were referred to specialized hypertension clinics (86 essential hypertension patients who had diastolic blood pressure > 100 mm Hg during antihypertensive treatment that included three or more antihypertensive drugs, one being a diuretic). Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed at the time of entrance. End-organ damage was monitored yearly, and the incidence of cardiovascular events was recorded. Patients were divided into tertiles of average diastolic blood pressure during activity according to the ABPM, with the lowest tertile <88 mm Hg (LT, n=29), the middle tertile 88 to 97 mm Hg (MT, n=29), and the highest tertile >97 mm Hg (HT, n=28). While significant differences in systolic and diastolic ambulatory blood pressures were observed among groups, no differences were observed at either the beginning or at the time of the last evaluation for office blood pressure. During the last evaluation, a progression in the end-organ damage score was observed for the HT group but not for the two other groups. Twenty-one of the patients had a new cardiovascular event; the incidence of events was significantly lower for the LT group (2.2 per 100 patient-years) than it was for the MT group (9.5 per 100 patient-years) or for the HT group (13.6 per 100 patient-years). The probability of event-free survival was also significantly different when comparing the LT group with the other two groups (LT versus MT log-rank, P<.04; LT versus HT log-rank, P<.006). The HT group was an independent risk factor for the incidence of cardiovascular events (relative risk, 6.20; 95% confidence interval, 1.38 to 28.1, P<.02). Higher values of ambulatory blood pressure result in a worse prognosis in patients with refractory hypertension, supporting the recommendation that ABPM is useful in stratifying the cardiovascular risk in patients with refractory hypertension.

Influence of the I/D polymorphism of the angiotensin-converting enzyme gene on the outcome of microalbuminuria in essential hypertension.

The objective of the present study was to analyze the influence of the I/D polymorphism of the ACE gene on the outcome of microalbuminuria in essential hypertensive patients who were receiving antihypertensive treatment. One hundred thirty-six essential hypertensive patients who were <50 years old and had never previously received treatment with antihypertensive drugs were included in the study. During a 3-year period, patients received nonpharmacological treatment consisting of moderate salt restriction and a low-calorie diet they were obese, with or without a regimen of antihypertensive drugs based on beta-blockers or ACE inhibitors. Hydrochlorothiazide was added when necessary to maintain the blood pressure goal of <135/85 mm Hg. At the beginning of the study and at yearly intervals, systolic and diastolic blood pressures (SBP and DBP, respectively), 24-hour urinary albumin excretion (UAE), renal function, and biochemical profile measurements were made. The insertion/deletion (I/D) polymorphism of the ACE gene was determined through the use of polymerase chain reaction. The variables used in the statistical analysis were the measurements at the start of the study and the increase or decrease detected during the follow-up, estimated as individual specific regression line slope values. At baseline, no differences in blood pressure or UAE values were observed among genotypes. Likewise, the genotype or allele frequency was not significantly different between normoalbuminurics and microalbuminurics. After the 3 treatment years, significant reductions in SBP, DBP, and UAE were found (SBP 151.6+/-17.3 reduced to 137.2+/-14.3 mm Hg, P<0.001; DBP 96.6+/-8.9 reduced to 84.5+/-9.8 mm Hg, P<0.001; UAE 36.7+/-71.5 reduced to 28.3+/-78.6 mg/24 h, P<0. 05). The slopes of these parameters over time did not differ significantly among genotypes. The slope of SBP was the main factor related to the slope of logUAE (P<0.003). A significant positive correlation coefficient between the SBP and logUAE slopes was observed for the DD patients (r=0.57, P<0.0001) but was absent in patients carrying the I allele (II r=-0.03, P=NS; I/D r=0.01, P=NS). Follow-up studies should be used to achieve a better understanding of the impact of candidate gene polymorphisms on the development of hypertension-induced organ damage. Assessment of the I/D polymorphism of the ACE gene may identify subjects who require a greatly lowered blood pressure to prevent organ damage and to reduce hypertension-associated complications and death.

Renal protection by antihypertensive drugs: insights from microalbuminuria studies.

During the last few years there has been a renewed interest in blood-pressure (BP)-induced kidney damage, owing to a progressive increase in the incidence and prevalence of hypertension and vascular diseases as a cause of end-stage renal disease (ESRD). The need to prevent ESRD demands continued efforts so as to identify early those people with hypertension who are at risk and to provide them with effective antihypertensive therapy. This review analyses what is needed in terms of surrogate endpoints for monitoring kidney damage and what is known about the impact of antihypertensive treatments in reducing the BP burden on the kidney in non-diabetic subjects. Although glomerular filtration rate (GFR) and proteinuria are useful surrogate endpoints for patients with nephropathy and GFR below or close to the threshold value for renal insufficiency, it is clear that monitoring changes in either GFR or proteinuria does not provide a sensitive endpoint for subjects with the mildest forms of renal disease, e.g. essential hypertensive patients who are at risk of developing kidney damage. In this case microalbuminuria may be useful, although unequivocal evidence demonstrating that microalbuminuria is a risk marker for developing renal insufficiency in non-diabetic renal diseases has not existed until now, and whether a decrease in microalbuminuria is of prognostic significance in patients with essential hypertension remains to be demonstrated. The beneficial effects of the antihypertensive agents on microalbuminuria are also proportional to BP reduction. If a large enough BP reduction is achieved there seem to be, at most, only minimal differences among the antihypertensive drug classes. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have additional beneficial effects on microalbuminuria independent of the BP reduction, owing to their direct role in glomerular haemodynamics. The heterogeneity in the changes in urinary albumin excretion during antihypertensive treatment may be related to the different factors involved in the presence of microalbuminuria or structural end-organ damage, or both.

The spectrum of circadian blood pressure changes in type I diabetic patients.

BACKGROUND: The objective of the present study was to characterize the spectrum of circadian blood pressure changes in type I diabetes at different stages of nephropathy by using two monitorings in each patient in order to avoid intra-individual variability. PATIENTS AND METHODS: A total of 80 type I diabetic subjects and the same number of age, sex and awake mean blood pressure (BP)-matched controls were included. According to urinary albumin excretion, there were 57 normoalbuminurics, 15 persistent microalbuminurics and eight proteinurics. Two 24 h ambulatory blood pressure monitorings were performed at the same urinary albumin excretion stage in absence of antihypertensive treatment for each diabetic subject and for their respective control. Blood pressure and heart rate averages during 24 h, awake, sleep, and day: night ratio were calculated. RESULTS: Seven of the eight proteinuric subjects were hypertensives, whereas hypertension was absent in the normoalbuminuric and microalbuminuric groups. The intraindividual reproducibility in diabetics showed repeatability coefficients for the 24 h systolic and diastolic pressure of 33 and 42%, respectively. This reproducibility for the day: night ratio was generally worse, 57% for systolic and 59% for diastolic. A progressive increment in the mean ambulatory BP was observed across the three groups of diabetics and the differences in BP observed were most evident during the night-time period. Though no differences in the 24 h circadian pattern were present between the normoalbuminurics and their controls, nocturnal differences were observed, not only in microalbuminurics for systolic BP (P < 0.05), but also in proteinurics for both systolic BP (P < 0.01) as well as diastolic BP (P < 0.05). No differences were observed in heart rate among the diabetic groups. The non-dipping pattern in the two monitorings was observed in 80, 58, 18 and 10% of the proteinurics, microalbuminurics, normoalbuminurics and control groups, respectively. CONCLUSIONS: Persistent abnormal circadian variability seems to be an early and frequent characteristic of type I diabetics with an increased urinary albumin excretion. Although present in some normalbuminuric subjects, the frequency of this abnormality increases as the incipient nephropathy progresses. By the time proteinuria is established, nearly all subjects present the abnormal pattern.

Ambulatory blood pressure and microalbuminuria in essential hypertension: role of circadian variability.

OBJECTIVE: To assess the relationship of subclinical urinary albumin excretion with ambulatory and circadian variability of blood pressure. DESIGN AND METHODS: Patients with essential hypertension (82 males and 59 females, mean +/- SD age 38.9 +/- 7.3 years) who had never been previously treated for hypertension were included in the study. Patients with nephropathy or diabetes mellitus, hyperglycemia > 120 mg/dl, glomerular filtration rate < 80 ml/min per 1.73 m2, urinary tract infection and positive dipstick for albumin or glucose were excluded. Twenty-four-hour ambulatory blood pressure monitoring on a regular working day using an oscillometric device was performed. Twenty-four-hour urinary albumin excretion was measured on two separate days using an immunonephelometric assay. RESULTS: Microalbuminuric patients (urinary albumin excretion 30-300 mg/24 h, n = 31) had significantly higher mean ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) than those with normoalbuminuria (urinary albumin excretion < 30 mg/24 h, n = 96) during the 24-h, daytime (0800-2200 h) and night (2400-0600 h) periods, whereas for office blood pressure only DBP was significantly higher. Urinary albumin excretion was positively correlated with the means of SBP and DBP. Multiple regression analysis similarly confirmed that DBP during daytime was positively and day:night ratio of DBP inversely associated with urinary albumin excretion independent of age, sex and other parameters of ambulatory blood pressure. CONCLUSIONS: In conclusion, the present study indicates that, in middle-aged essential hypertensive patients, the presence of microalbuminuria is a marker for the presence of higher values of blood pressure throughout a 24-h period.