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Elevated blood pressure remains a major cause of cardiovascular disease, disability, and premature death in Austria, with suboptimal rates of detection, treatment and control also in recent years. Management of hypertension is a common challenge for physicians with different spezializations. In an attempt to standardize diagnostic and therapeutic strategies and, ultimately, to increase the rate of patients with controlled blood pressure and to decrease the burden of cardiovascular disease, 13 Austrian medical societies reviewed the evidence regarding prevention, detection, workup, treatment and consequences of high blood pressure in general and in various clinical scenarios. The result is presented as the first national consensus on blood pressure. The authors and societies involved are convinced that a joint national effort is needed to decrease hypertension-related morbidity and mortality in our country.

Over the past 5 years several case reports and cohort studies have been published that describe a sprue-like enteropathy (SLE) with abdominal pain, chronic diarrhea and weight loss, after taking angiotensin type 1 receptor blockers (ARB). The initial case series from the Mayo Clinic, which described 22 cases of olmesartan-induced SLE, was followed by numerous case descriptions for almost all ARBs. A total of 73 case reports have been described so far that show evidence of ARB-associated enteropathy with villous atrophy and full recovery 3–12 months after discontinuation of the sartan in question. Of these, 59 cases were olmesartan-associated cases of SLE, another 14 case reports have been published for telmisartan (4), valsartan (3), losartan (2), candesartan (1) and eprosartan (1). Based on the available cohort studies, ARB-associated intestinal malabsorption occurs in 9.8–14 cases per 100,000 patients treated with ARBs, the number treated to harm is over 31,000 patient-years. Although the majority of case reports have been published with olmesartan, in the cohort studies no clear difference within the ARBs can be ruled out. The SLE is rare but must be suspected and diagnostically investigated in every patient presenting with abdominal discomfort, chronic diarrhea and weight loss who is being treated with an ARB, after other causes have been ruled out. In such cases, discontinuing the ARB leads to a full recovery.

High blood pressure is a major modifiable risk factor for all clinical manifestations of coronary artery disease (CAD). In people without known cardiovascular disease, the lowest systolic (down to 90-114 mmHg) and the lowest diastolic (down to 60-74 mmHg) pressures are associated with the lowest risk for developing CAD. Although diastolic blood pressure is the strongest predictor of CAD in younger and middle-aged people, this relationship becomes inverted and pulse pressure shows the strongest direct relationship with CAD in people above 60 years of age.Pathophysiological mechanisms of blood pressure as a risk factor for CAD are complex and include the influence of blood pressure as a physical force on the development of the atherosclerotic plaque, and the relationship between pulsatile hemodynamics/arterial stiffness and coronary perfusion. Treatment of arterial hypertension has been proven to prevent coronary events in patients without clinical CAD. In patients with established CAD, the effect of blood pressure lowering per se is beneficial, probably more than specific drugs or drug classes. The important exceptions are beta blockers (BBs), which are superior to all other drug classes for use after a recent myocardial infarction. Blood pressure targets in patients with established CAD have created controversy in the light of the so-called J-curve phenomenon, which describes an increase in coronary events at lower diastolic blood pressures. One explanation for this observation is that perfusion of the left ventricle occurs predominantly during diastole, and that coronary autoregulation may be exhausted with low diastolic blood pressure in the setting of left ventricular hypertrophy and atherosclerotic narrowing of the epicardial coronaries. The worst situation is a high systolic blood pressure in the presence of a low diastolic blood pressure, both a hallmark of increased aortic stiffness. However, the lowering of systolic blood pressure is clearly beneficial in this setting, even at the price of further lowering diastolic pressure. Primary blood pressure goal in patients with established CAD is below 140/90 mmHg. Recent studies suggest that a lower systolic blood pressure may be appropriate, whereas caution is advised with diastolic blood pressure below 60 mmHg.

Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.

Clinical disorders with an isolated lack of monocytes have not been reported hitherto. The authors describe the case of a 38-year-old woman with pulmonary alveolar proteinosis and nephrotic syndrome caused by membranous nephropathy and widespread papillomatosis of the vulva. Immunologic studies showed normal levels of immunoglobulins and C2, C3c, and C4. Cryoglobulins and paraproteins were not detected. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, and antiglomerular basement membrane antibodies were not detectable. Circulating immune complexes containing C1q, immunoglobulin G, and immunoglobulin M were elevated. The patient showed immunodeficiency that was characterized by complete anergy to intracutaneously administered recall antigens in vivo and to recall antigens in vitro. The immunodeficiency was accompanied by the absence of monocytes in the peripheral blood as well as in bone marrow cultures. In parallel, long-term bone marrow cultures and colony-forming cell assays did not result in the growth of monocytes. Mitogenic agents that require the presence of monocytes induced almost no T-cell proliferation (Concanavalin A: 5,841 counts per minute [cpm]), whereas agents that act directly on T cells induced intense T-cell proliferation (phytohemagglutinin: 110,001 cpm; OKT 3: 120,616 cpm; and pokeweed mitogen: 89,474 cpm). These data suggest that the pulmonary renal syndrome in this patient results from the lack of monocytes and the consecutive defect of antigen presentation and antigen clearance.

Arterial stiffening is the major cause of increasing systolic blood pressure in arterial hypertension. Increased arterial stiffness is one major mechanism responsible for morbidity and mortality in hypertension. A C825T polymorphism was identified in the gene encoding the G-protein beta3 subunit (GNB3), and an association of the T-allele with hypertension was demonstrated in several studies. In order to identify a pathogenetic link between hypertension and arterial stiffness, we compared two indices of arterial stiffness, pulse wave velocity (PWV) and augmentation index, in young, healthy men with and without the 825T-allele under resting conditions. PWV was determined from pressure tracing over carotid and femoral arteries in 99 subjects (CC: n=43; CTTT: n=56). Augmentation index was derived in 72 subjects (CC: n=30; CTTT: n=42) by pulse wave analysis using radial applanation tonometry. Carriers of the 825T-allele exhibited a significantly higher PWV compared to subjects with the CC genotype (6.0+/-0.1 m/s (TCTT) vs 5.7+/-0.1 m/s (CC); P=0.0251). There was also a significant difference (P = 0.0448) in augmentation index between carriers of the T-allele (CTTT: 3.4+/-2.9%) and controls with the CC -genotype (-5.0+/-4.1 %). There was no difference in any other anthropometric (age, height, weight, body mass index) or haemodynamic (heart rate, peripheral and central blood pressure). In summary, the C825T polymorphism is associated with higher arterial stiffness in young, healthy males. Arterial stiffening may pathogenetically contribute to the development of hypertension in carriers of the T-allele.

Background A C825T polymorphism was recently identified in the gene encoding the β3 subunit of heterotrimeric G-proteins (GNB3). The T-allele is significantly associated with essential hypertension and obesity. In order to further explore a possible pathogenetic link between the T-allele and impaired glucose tolerance we studied metabolic and haemodynamic responses to oral glucose loading in young, healthy subjects with and without the 825T-allele. Methods Twelve subjects with and 10 without the 825T-allele were investigated at rest and following glucose ingestion (75 g). Blood glucose, serum insulin and haemodynamics were determined prior to and over 2 hours following glucose ingestion. We non-invasively measured stroke volume (SV, by impedance-cardiography), blood pressure (BP), heart rate (HR), and systolic-time-intervals. Cardiac output (CO) was calculated from HR and SV. Total peripheral resistance was calculated from CO and BP. Metabolic and haemodynamic changes were quantified by maximal responses and by calculation of areas under the concentration time profile (AUC). Significances of differences between subjects with and without the T-allele were determined by unpaired two-tailed t-tests. A p < 0.05 was considered statistically significant. Results Metabolic and haemodynamic parameters at baseline were very similar between both groups. The presence of the T-allele did not alter the response of any metabolic or haemodynamic parameter to glucose loading. Conclusions In conclusion, this study does not support the hypothesis that the C825T polymorphism may serve as a genetic marker of early impaired glucose tolerance.

The T allele of the C825T polymorphism in the gene encoding the G-protein β3 subunit (GNB3) is associated with hypertension. An enhanced signal transduction in response to α2-adrenergic receptor stimulation has been shown in carriers of the T allele in vitro. We hypothesized that T allele carriers would show an enhanced antihypertensive response to stimulation of central α2-adrenergic receptors by clonidine. We compared the response to intravenous clonidine in 30 young, healthy male subjects with and without the T allele (15 CC, 10 CT, and 5 TT). Clonidine lowered blood pressure and total peripheral resistance, lengthened the duration of electromechanical systole (QS2c), and slowed down pulse wave velocity. Carriers of the T allele showed significantly greater reductions in systolic blood pressure (P = .009; mean change ± SEM: CC, −8.9 ± 0.5; CT and TT, −10.6 ± 0.4) and total peripheral resistance (P < .0001; mean change ± SEM: CC, 40 ± 17; CT and TT, −48 ± 14) and more marked lengthening of QS2c (P = .002; mean change ± SEM: CC, 2.2 ± 0.5; CT and TT, 4.7 ± 0.6) and slowing of pulse wave velocity (P = .012; mean change ± SEM: CC, −0.25 ± 0.02; CT and TT, −0.33 ± 0.03). The results of this study suggest that the 825T allele may be a relevant pharmacogenetic marker in the use of centrally acting sympatholytic drugs. Clinical Pharmacology & Therapeutics (2003) 74, 53–60; doi: 10.1016/S0009-9236(03)00087-0

Over the last decades, kidney transplantation has developed into a standard treatment for end-stage renal failure. This was made possible by a variety of medical achievements such as marked improvements in immunosuppressive regimens. Unfortunately, immunosuppressive drugs always bear the risk of infectious diseases. One of the most frequent infectious agents in the wake of transplantation is cytomegalovirus (CMV). CMV belongs to the group of herpes viruses and about 80% of adults are carriers. Whether or not CMV disease develops after transplantation depends on a variety of factors, particularly whether or not the donor anduor recipient are carriers of the virus w1x.

The concept to use the human skin microcirculation as a pharmacological in-vivo test system is old; however, methods developed in the 50s have been abandoned because of side effects and/or use of radioactive substances. We describe a newly developed minimally invasive method that allows in-vivo pharmacology in the human skin microcirculation injecting very low doses of a substance or drug without any systemic effects. The double injection technique (DIT) bears the potential to predict the effects of a drug and/or the vascular reactivity or dysfunction of other less accessible areas of the circulation (e. g. the myocardium). The DIT has been applied for studies in healthy volunteers and patients with atherosclerosis; the focus of interest was endothelial (dys-) function and the effect of exogenous vasoactive drugs. Using endothelin antagonists, we investigated the role of endogenous endothelin under physiological conditions and in atherosclerosis. The NO-synthase inhibitor L-NMMA has been applied to study the L-arginine-NO-pathway and the role of endothelial adrenoceptors. Ongoing studies with the DIT comparing coronary and skin microcirculation may help to develop minimally invasive methods to predict the effects of drugs and vascular function in the heart.