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Background: Left ventricular assist devices (LVADs) are increasingly used for the treatment of advanced heart failure. LVADs improve quality of life and decrease mortality, but the driveline carries substantial risk for major infections. These device-related LVAD and driveline infections are difficult to diagnose with conventional imaging. We reviewed and analysed the current literature on the additive value of 18 F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) imaging for the diagnosis of LVAD-related infections.", Materials/methods: We performed a systematic literature review using several databases from their inception until the 31st of December, 2019. Studies investigating the diagnostic performance of FDG-PET/CT in patients with suspected LVAD infection were retrieved. After a bias risk assessment using QUADAS-2, a study-aggregate meta-analysis was performed on a per examination-based analysis., Results: A total of 10 studies were included in the systematic review, eight of which were also eligible for study-aggregate meta-analysis. For the meta-analysis, a total of 256 FDG-PET/CT scans, examining pump/pocket and/or driveline infection, were acquired in 230 patients. Pooled sensitivity of FDG-PET/CT was 0.95 (95% confidence interval (CI) 0.89-0.97) and pooled specificity was 0.91 (95% CI 0.54-0.99) for the diagnosis of device-related infection. For pump/pocket infection, sensitivity and specificity of FDG-PET/CT were 0.97 (95%CI 0.69-1.00) and 0.93 (95%CI 0.64-0.99), respectively. For driveline infection, sensitivity and specificity were 0.96 (95%CI 0.88-0.99) and 0.99 (95%CI 0.13-1.00) respectively. Significant heterogeneity existed across studies for specificity, mostly caused by differences in scan procedures. Predefined criteria for suspicion of LVAD and/or driveline infection were lacking in all included studies., Conclusions: FDG-PET/CT is a valuable tool for assessment of device-related infection in LVAD patients, with high sensitivity and high, albeit variable, specificity. Standardization of FDG-PET/CT procedures and criteria for suspected device-related LVAD infections are needed for consistent reporting of FDG-PET/CT scans.

Background: Multimodality imaging is recommended to diagnose infective endocarditis. Value of additional imaging to echocardiography in patients selected by a previously proposed flowchart has not been evaluated., Methods: An observational single-center study was performed. Adult patients suspected of endocarditis/device infection were prospectively and consecutively enrolled from March 2016 to August 2017. Adherence to a diagnostic imaging-in-endocarditis-flowchart was evaluated in 176 patients. Imaging techniques were compared head-to-head in 46 patients receiving echocardiography (transthoracic plus transesophageal), multi-detector computed tomography angiography (MDCTA), and 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT)., Results: 69% of patients (121/176) adhered to the flowchart. Sensitivity of echocardiography, MDCTA, FDG-PET/CT in patients without prosthesis was 71%, 57%, 29% (86% when combined), while specificity was 100%, 75%, 100%, respectively. Sensitivity in patients with prosthesis was 75%, 75%, 83%, respectively (100% when combined), while specificity was 86% for all three modalities. Echocardiography performed best in the assessment of vegetations, morphological valve abnormalities/dehiscence, septum defects, and fistula formation. MDCTA performed best in the assessment of abscesses and ventricular assist device infection. FDG-PET/CT performed best in the assessment of cardiac device infection, extracardiac infectious foci, and alternative diagnoses., Conclusions: This study demonstrates that the evaluated imaging-in-endocarditis-flowchart is applicable in daily clinical practice. Echocardiography, MDCTA, and FDG-PET/CT provide relevant complementary diagnostic information, particularly in patients with intracardiac prosthetic material.

Background: 18 F-Fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) was recently introduced as a new tool for the diagnosis of prosthetic heart valve endocarditis (PVE). Previous studies reporting a modest diagnostic accuracy may have been hampered by unstandardized image acquisition and assessment, and several confounders, as well. The aim of this study was to improve the diagnostic performance of FDG PET/CT in patients in whom PVE was suspected by identifying and excluding possible confounders, using both visual and standardized quantitative assessments., Methods: In this multicenter study, 160 patients with a prosthetic heart valve (median age, 62 years [43-73]; 68% male; 82 mechanical valves; 62 biological; 9 transcatheter aortic valve replacements; 7 other) who underwent FDG PET/CT for suspicion of PVE, and 77 patients with a PV (median age, 73 years [65-77]; 71% male; 26 mechanical valves; 45 biological; 6 transcatheter aortic valve replacements) who underwent FDG PET/CT for other indications (negative control group), were retrospectively included. Their scans were reassessed by 2 independent observers blinded to all clinical data, both visually and quantitatively on available European Association of Nuclear Medicine Research Ltd-standardized reconstructions. Confounders were identified by use of a logistic regression model and subsequently excluded., Results: Visual assessment of FDG PET/CT had a sensitivity/specificity/positive predictive value/negative predictive value for PVE of 74%/91%/89%/78%, respectively. Low inflammatory activity (C-reactive protein <40 mg/L) at the time of imaging and use of surgical adhesives during prosthetic heart valve implantation were significant confounders, whereas recent valve implantation was not. After the exclusion of patients with significant confounders, diagnostic performance values of the visual assessment increased to 91%/95%/95%/91%. As a semiquantitative measure of FDG uptake, a European Association of Nuclear Medicine Research Ltd-standardized uptake value ratio of ≥2.0 was a 100% sensitive and 91% specific predictor of PVE., Conclusions: Both visual and quantitative assessments of FDG PET/CT have a high diagnostic accuracy in patients in whom PVE is suspected. FDG PET/CT should be implemented early in the diagnostic workup to prevent the negative confounding effects of low inflammatory activity (eg, attributable to prolonged antibiotic therapy). Recent valve implantation was not a significant predictor of false-positive interpretations, but surgical adhesives used during implantation were.

Background: Surgical treatment of complicated aortic valve endocarditis often is challenging, even for experienced surgeons. We aim at demonstrating a standardized surgical approach by stentless bioprostheses for the treatment of aortic valve endocarditis complicated by paravalvular abscess formation., Methods: Sixteen patients presenting with aortic valve endocarditis (4 native and 12 prosthetic valves) and paravalvular abscess formation at various localizations and to different extents were treated by a standardized approach using stentless bioprostheses. The procedure consisted of thorough debridement, root replacement with reimplantation of the coronary arteries and correction of accompanying pathologies (aortoventricular and aortomitral dehiscence, septum derangements, Gerbode defect, total atrioventricular conduction block, mitral and tricuspid valve involvement)., Results: All highly complex patients included (14 males and 2 females; median age 63 years [range 31-77]) could be successfully treated with stentless bioprostheses as aortic root replacement. Radical surgical debridement of infected tissue with anatomical recontruction was feasible. Although predicted operative mortality was high (median logarithmic EuroSCORE I of 40.7 [range 12.8-68.3]), in-hospital and 30-day mortality rates were favorable (18.8 and 12.5% respectively)., Conclusions: Repair of active aortic valve endocarditis complicated by paravalvular abscess formation and destruction of the left ventricular outflow tract with stentless bioprosthesis is a valuable option for both native and prosthetic valves. It presents a standardized approach with a high success rate for complete debridement, is readily available, and yields comparable clinical outcomes to the historical gold standard, repair by homografts. Additionally, use of one type of prosthesis reduces logistical issues and purchasing costs.

Several diagnostic imaging methodologies are available for the clinical evaluation of sarcoidosis, but all have their limitations. FDG PET/CT is frequently used, but this technique does not provide optimal results in all cases. Novel radiopharmaceuticals aimed at other disease targets may be helpful, particularly in cardiac sarcoidosis when FDG PET/CT has a low diagnostic accuracy, due to difficulties in preparing the patients who should use a specific diet combined with prolonged fasting. 68 Ga-labeled somatostatin based receptor hybrid imaging is a potential alternative to FDG PET/CT. This short communication provides a rapid overview of initial findings concerning the application of 68 Ga-labeled somatostatin based receptor hybrid imaging in the diagnosis of (cardiac) sarcoidosis activity., Competing Interests: Informed consent was not required (since this is a retrospective study).The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Sensitivity and specificity of the modified Duke criteria for native valve endocarditis are both suboptimal, at approximately 80%. Diagnostic accuracy for intracardiac prosthetic material-related infection is even lower. Non-invasive imaging modalities could potentially improve diagnosis of infective endocarditis; however, their diagnostic value is unclear. We did a systematic literature review to critically appraise the evidence for the diagnostic performance of these imaging modalities, according to PRISMA and GRADE criteria. We searched PubMed, Embase, and Cochrane databases. 31 studies were included that presented original data on the performance of electrocardiogram (ECG)-gated multidetector CT angiography (MDCTA), ECG-gated MRI, 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT, and leucocyte scintigraphy in diagnosis of native valve endocarditis, intracardiac prosthetic material-related infection, and extracardiac foci in adults. We consistently found positive albeit weak evidence for the diagnostic benefit of 18 F-FDG PET/CT and MDCTA. We conclude that additional imaging techniques should be considered if infective endocarditis is suspected. We propose an evidence-based diagnostic work-up for infective endocarditis including these non-invasive techniques., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: It has been suggested that home-based heart failure (HF) management in primary care may be an alternative to clinic-based management in HF patients. However, little is known about adherence to HF guidelines and adherence to the medication regimen in these home-based programmes. The aim of the current study was to determine whether long-term follow-up and treatment in primary care is equally effective as follow-up at a specialized HF clinic in terms of guideline adherence and patient adherence, in HF patients initially managed and up-titrated to optimal treatment at a specialized HF clinic., Methods and Results: We conducted a multicentre, randomized, controlled study in 189 HF patients (62% male, age 72 ± 11 years), who were assigned to follow-up either in primary care (n = 97) or in a HF clinic (n = 92). After 12 months, no differences between guideline adherence, as estimated by the Guideline Adherence Indicator (GAI-3), and patient adherence, in terms of the medication possession ratio (MPR), were found between treatment groups. There was no difference in the number of deaths (n = 12 in primary care and n = 8 in the HF clinic; P = 0.48), and hospital readmissions for cardiovascular (CV) reasons were also similar. The total number of unplanned non-CV hospital readmissions, however, tended to be higher in the primary care group (n = 22) than in the HF clinic group (n = 10; P = 0.05)., Conclusions: Patients discharged after initial management in a specialized HF clinic can be discharged to primary care for long-term follow-up with regard to maintaining guideline adherence and patient adherence. However, the complexity of the HF syndrome and its associated co-morbidities requires continuous monitoring. Close collaboration between healthcare providers will be crucial in order to provide HF patients with optimal, integrated care., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

An 82-year-old woman presented with dyspnoea and palpitations. The patient was admitted to the cardiology ward on suspicion of atrial fibrillation and reduced cardiac output. Examination revealed position-dependent deoxygenation. Once acute cardiac or pulmonary pathologies were excluded a diagnosis of platypnea-orthodeoxia was considered. Diagnosis was confirmed by transoesophageal contrast echocardiography, which showed a patent foramen ovale. Curative treatment consisted of percutaneous closure of the foramen ovale. A persistent asymptomatic foramen ovale is common and can be revealed in later life. Platypnea-orthodeoxia syndrome is a relatively unfamiliar disorder.

In this brief report we present a patient with heterozygous alpha2 plasmin inhibitor (alpha2PI) deficiency who developed atherosclerosis and myocardial ischemia in the presence of multiple classical risk factors. Management was complicated by fear of bleeding complications with the use of antiplatelet agents and serious comorbidity.The role of alpha2PI in atherosclerosis and pathological clot formation is still not clear. This case shows, however, that atherosclerosis and acute cardiovascular events can develop in patients with reduced alpha2PI levels.

Introduction: Mycotic aneurysm of the aorta is a rare diagnosis with high mortality., Report: Percutaneous coronary intervention was complicated by bacteraemia with Staphylococcus aureus and a mycotic aortic aneurysm, an unusual complication of coronary angiography. Combining CT and PET scan showed a hotspot in the thoracic aorta. After six months of antibiotic treatment she fully recovered. Repeated CT/PET scanning revealed complete abolishment of the aortic abnormalities., Discussion: This report suggests that diagnosing and follow-up of aortitis is feasible with combined CT/PET scan and may help in determining choice and duration of therapy.

Introduction: Animal studies demonstrated an interaction between angiotensin II (Ang II) responsiveness and endothelium-dependent relaxation (EDR). However, this relation has not been well described in humans. Therefore, we investigated the relation between Ang II responsiveness and EDR in isolated human arteries., Materials and Methods: Segments of the internal mammary artery (IMA) were harvested from 89 patients undergoing coronary bypass surgery. Rings of these segments were exposed in organ bath experiments to metacholine (ME; 10 nmol/L-0.1 mmol/L) after precontraction with phenylephrine (PE; 10 micromol/L), and secondly to increasing concentrations of Ang II (0.1 nmol/L-1 micromol/L)., Results: Patients with the highest contraction to Ang II showed the lowest ME relaxation (r=0.312; p=0.003). Angiotensin-converting enzyme (ACE)-inhibition significantly increased Ang II sensitivity (p=0.03). This increase was accompanied by a tendency toward decreased EDR (p=0.07). The inverse relation between Ang responsiveness and endothelium-dependent relaxation could not be explained by an increased tissue or serum ACE-inhibition in patients with a higher endothelium-dependent relaxation., Conclusions: High Ang II responsiveness inversely correlates to EDR in IMA's of patients with established coronary artery disease. Short-term treatment with an ACE-inhibitor increased the response to Ang II, but had an adverse effect on EDR.

Background: Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two., Methods and Results: We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, P<0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo., Conclusions: Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-beta signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

Introduction: The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described., Materials and Methods: In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries., Results: In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2+/-5.11% [n=13] vs. 55.6+/-4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar between DD- and ID/II-genotype (59.6+/-9.19% [n=8] vs. 57.7+/-4.07% [n=35]; p=0.85)., Conclusions: DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.

Objective: to examine the effect of angiotensin converting enzyme inhibition (ACEI) on soluble intercellular adhesion molecule 1 (sICAM-1) and C-reactive protein (CRP) in patients requiring coronary artery bypass grafting (CABG)., Method: subgroup analysis of 42 patients randomised to Quinapril (40 mg daily determined) and 45 to placebo. sICAM-1 and CRP were > or = 4 weeks before and 1 year after surgery., Results: there was no difference in sICAM-1 at baseline (142.2 microg/L vs 136.6 microg/L). There was significant reduction in s-ICAM-1 in patients receiving quinapril (142.2+/-10.8 microg/L vs 125.6+/-9.4 microg/L, p<0.05) but not placebo (136.6+/-10.2 microg/L vs 131.2+/-11.7 microg/L, p=NS). Levels of C-reactive protein remained unchanged in both groups (3.70+/-0.85 vs 2.73+/-0.32 mg/L, 2.85+/-0.48 vs 3.16+/-0.50 mg/L)., Conclusions: ACEI reduces sICAM-1 in patients undergoing CABG. The benefits of ACEI may partly be due to a reduction of the vascular inflammatory response.

Angiotensin II induces ischemia/reperfusion (I/R)-induced arrhythmias and blockade of the angiotensin II type 1 receptor (AT1R) may therefore be beneficial in preventing arrhythmias and decreasing mortality after myocardial infarction (MI). Because the AT1R is upregulated after myocardial ischemia, it was hypothesized that the level of AT1R expression would mediate the response to AT1R blockade. Transgenic (TGR) rats that overexpress the human AT1R and Sprague-Dawley rats were used as controls. Total duration of arrhythmia (seconds) after I/R injury was similar in TGR and SD rats (433 +/- 109 vs. 376 +/- 117, p = n.s.). AT1R blockade with losartan decreased total duration of arrhythmia in the TGR rats (433 +/- 110 s-164 +/- 48 s; p < 0.05), whereas it caused a nonsignificant increase in the SD rats (376 +/- 117 s-497 +/- 97). In vivo, survival in the first 24 hours after MI was impaired in TGR rats (39%; SD, 63%). Losartan improved survival significantly in TGR rats (from 39% to 80%, p < 0.05). A smaller, nonsignificant effect was observed in SD rats (63% to 81%). AT1R blockade is beneficial only when the AT1R was overexpressed, both in reducing the reperfusion-induced arrhythmias and mortality early after MI.

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.

Objective: To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT(1)R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis., Design: Prospective defined substudy of the lipid lowering regression trial (REGRESS)., Setting: University hospital., Patients: 885 male patients with stable coronary artery disease., Main Outcome Measures: Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years., Results: Patients who carried both the ACE-DD and AT(1)R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years., Conclusions: The suggestion that ACE-DD and AT(1)R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.

An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT(1)R) gene is associated with the incidence of essential hypertension and increased coronary artery vasoconstriction. However, it is still unknown whether this polymorphism is associated with a difference in angiotensin II responsiveness. Therefore, we assessed whether the AT(1)R polymorphism is associated with different responses to angiotensin II in isolated human arteries. Furthermore, we evaluated whether inhibition of the renin-angiotensin system modifies the effect of the AT(1)R polymorphism. One hundred twelve patients who were undergoing coronary artery bypass graft surgery were prospectively randomized to receive an ACE inhibitor or a placebo for 1 week before surgery. Excess segments of the internal mammary artery were exposed to angiotensin II (0.1 nmol/L to 1 micromol/L) and KCl (60 mmol/L) in organ bath experiments. Patients homozygous for the C allele (n=17) had significantly greater angiotensin II responses (percentage of this maximal KCl-induced response) than did patients genotyped with AA+AC (n=95, P<0.05). Although ACE inhibition increased the response to angiotensin II, the difference in the response to angiotensin II, between CC and AA+AC patients remained intact in ACE inhibitor-treated patients. These results indicate increased responses to angiotensin II in patients with the CC genotype. The mechanism is preserved during ACE inhibition, which in itself also increased the response to angiotensin II. This reveals that the A1166C polymorphism may be in linkage disequilibrium with a functional mutation that alters angiotensin II responsiveness, which may explain the described relation between this polymorphism and cardiovascular abnormalities.

In the present review, we discuss the role of clinical dosing of angiotensin converting enzyme (ACE) inhibitors in the treatment of left ventricular dysfunction. Although the precise mechanism of action of ACE inhibitors is still unresolved, the clinical efficacy of ACE inhibitors in the treatment of left ventricular dysfunction is well established. However, it is unclear whether the doses used in clinical trials translate directly into daily practice. Several reasons may cause differences between clinical practice and controlled trials: (1) clinical trials used higher doses than in normal practice; (2) some patients may be relatively 'resistant' to ACE inhibition; and/or (3) ACE activity increases during ACE inhibitor therapy and may provide escape mechanisms when the drug regimen is not strictly adhered to. Therefore, it is of interest that recent trials suggest that only the higher doses of ACE inhibition are clinically efficacious. In conclusion, it is suggested that optimal benefit from treatment with an ACE inhibitor in patients with left ventricular dysfunction requires sufficient and frequent dosing of the ACE inhibitor, e.g., enalapril 10 mg twice daily or captopril 25 mg three times daily.

The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC(50) of 3.0 and 4.0 micromol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro(11),D-Ala(12)]-angiotensin I were antagonized by angiotensin-(1-7) (10(-5) mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro(10)]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system.

Peptides produced by the renin-angiotensin system play a major role in the development and progression of various cardiovascular diseases. One of these peptides, angiotensin II, is a potent vasoconstrictor that exerts most of its effects through the human AT1 receptor. Following the discovery of a functional variation in the angiotensin-converting enzyme gene, research has identified other genetic variations in the renin-angiotensin system that may contribute to cardiovascular disorders. Of the described polymorphisms in the AT1-receptor gene, the A1166C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT1) rat model, which overexpresses the human AT1 receptor in the myocardium, to study some of the associations between an increased AT1-receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT1 receptor causes no changes in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT1-receptor polymorphism may not cause cardiovascular disorders directly, it can perhaps contribute to a process that is started by other factors, such as increased activity or uptake by tissues of plasma renin, which leads to local activation of the renin-angiotensin system. Our data indicate that the AT1-receptor polymorphism is probably associated with an increased responsiveness to angiotensin II. Under basal conditions, this increased responsiveness does not seem to affect the heart, but it may exert adverse effects under loading or high-renin conditions.

Objectives: To use the autologous gastroepiploic artery (GEA) as arterial bypass graft for peripheral revascularisation. We compared the development of intimal hyperplasia and nitric oxide (NO) capacity in GEA and internal jugular vein (IJV) implanted as peripheral grafts., Materials and Methods: In pigs the GEA was implanted into the right peripheral circulation as a femoropopliteal bypass graft. In the left peripheral circulation the IJV was implanted as a femoropopliteal graft. After 21 days all grafts were harvested. Vascular rings of each graft before and after operation were studied for NO capacity. The distal half of each graft was prepared for histomorphometric studies., Results: Administration of bradykinin to IJV and GEA induced relaxation. After implantation bradykinin resulted in contraction in IJV grafts, whereas in GEA grafts relaxation was reduced. In IJV grafts extensive intimal hyperplasia was formed, whereas in GEA grafts only small areas of intimal hyperplasia were formed., Conclusions: The functional studies lost NO capacity in IJV grafts, whereas NO capacity in GEA grafts remained intact. Intimal hyperplasia in IJV grafts was extensive, whereas GEA grafts demonstrated preservation of pre-existent intimal architecture. These results may encourage the application of the human GEA as bypass graft for reconstruction of arteries in the lower limb or foot.

To compare hypertensive end-organ damage in two genetic forms of hypertension we assessed cardiovascular function in two rat strains of genetic hypertension: transgenic rats overexpressing the mouse Ren-2 gene [(TGR(mREN2)27]) and blood pressure matched spontaneously hypertensive rats (SHR). Despite similarly elevated blood pressure, systolic dp/dt (mmHg/s) was more impaired in transgenic rats (3099 +/- 446) than in SHR (3571 +/- 272) and normals (4342 +/- 119; P < 0.05). Left ventricular weight (mg/g body weight) increased more in the transgenic rats (40 +/- 3) than in SHR (31 +/- 2) and normals (26 +/- 2). Endothelium-dependent relaxation was significantly decreased only in the transgenic rats. This study shows significantly more cardiac and endothelial dysfunction in transgenic, hypertensive TGR (mREN2)27 than in age and blood pressure matched SHR. This supports the hypothesis that chronic activation of the renin-angiotensin system significantly contributes to hypertensive end-organ damage.

Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.