The value of 18F-FDG PET/CT for the diagnosis of device-related infections in patients with a left ventricular assist device: a systematic review and meta-analysis.

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 18F-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.

Mycotic aneurysm of the aorta as an unusual complication of coronary angiography.

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.

Long term angiotensin converting enzyme-inhibition in patients after coronary artery bypass grafting reduces levels of soluble intercellular cell adhesion molecule-1.

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.

Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy.

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.

Increased risk for ischaemic events is related to combined RAS polymorphism.

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.

Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries.

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.

Dosing of ACE inhibitors in left ventricular dysfunction: does current clinical dosing provide optimal benefit?

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.

Angiotensin-(1-7) is a modulator of the human renin-angiotensin system.

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.

Is the A1166C polymorphism of the angiotensin II type 1 receptor involved in cardiovascular disease?

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.

The use of the gastroepiploic artery for peripheral revascularisation. A study in pigs.

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.

Differential inhibition of plasma versus tissue ACE by utibapril: biochemical and functional evidence for inhibition of vascular ACE activity.

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.

Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats.

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.