Combined evaluation of myocardial perfusion and coronary morphology in the identification of subclinical CAD. Radiation exposure of 13N-ammonia PET/CT.

PURPOSE: to evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECG-pulsing CT angiography (CTA) in the evaluation of myocardial perfusion, myocardial blood flow (MBF) and coronary morphology for the identification of subclinical CAD. PATIENTS, MATERIAL, METHODS: following rest-stress 13N-ammonia PET/CT perfusion imaging and MBF quantification, ECG-pulsing CTA at a pulse window of 70% of the R-R cycle was performed in ten healthy controls and in sixteen individuals with cardiovascular risk factors. Individual radiation dose exposure for ECG-pulsing CTA was estimated from the dose-length product. RESULTS: PET demonstrated normal perfusion in all study individuals, while hyperemic MBFs during dipyridamole stimulation and the myocardial flow reserve (MFR) in cardiovascular risk individuals were significantly lower than in healthy controls (1.34±0.26 vs. 2.28±0.47 ml/g/min and 1.48±0.39 vs. 3.24±0.81, both p≤0.0001). Further, ECG-pulsing CTA identified mild calcified and non-calcified coronary plaque burden in 7 (43%) individuals of the cardiovascular risk group. Rest-stress 13N-ammonia PET/CT perfusion study yielded a mean effective radiation dose of 3.07±0.06 mSv (2.07±0.06 mSv from the rest-stress 13N-ammonia injections and 1.0 mSv from the 2 CT transmission scans), while ECG-pulsing CTA was associated with 5.57±2.00 mSv. The mean effective radiation dose of the combined 13N-ammonia PET/CT and ECG-pulsing CTA exams in the evaluation of myocardial perfusion and coronary morphology was 8.0±1.5 mSv. CONCLUSION: 13N-ammonia PET/CT and ECG-pulsing CTA affords cardiac hybrid imaging studies in the evaluation of subclinical CAD with a relatively low mean effective radiation exposure of 8.0±1.5mSv.

Novel treatment strategy with direct renin inhibition against heart failure.

Non-uniformity exists on heart failure definitions. Heart failure includes typical signs and symptoms deriving from alterations in left ventricular systolic or diastolic function. Systolic heart failure results from the acute or chronic reduction of the left ventricular ejection fraction. Conversely, heart failure with preserved ejection fraction is characterized by excessive myocardial fibrosis and cardiomyocyte hypertrophy that cause reduced left ventricular relaxation. Both heart failure subtypes cause identical symptoms and signs. Clinical and laboratory tests assist in the diagnosis of systolic heart failure or heart failure with preserved ejection fraction (diastolic heart failure) and can help in the identification of different causes of the disease and comorbidities. In the last two decades, the renin-angiotensin system (RAS) has been identified as a crucial regulator in all phases of systolic and diastolic heart failure. Although several studies are needed to further clarify this issue, three different levels (systemic, intracardiac and intracellular) for renin pathophysiological activity have been identified. In particular, the direct role of intracellular renin on subcellular cardiomyocyte remodeling could be considered as a very fruitful investigation field. Several ongoing clinical studies will probably clarify the role of renin inhibitors in heart failure. The ancient theory of Skeggs and coworkers on direct renin inhibition to block the RAS cascade effects could be confirmed in future studies.

Chlorhexidine prevents hypochlorous acid-induced inactivation of alpha1-antitrypsin.

1. Chlorhexidine digluconate has been used as a topical antiseptic in the treatment of acne vulgaris and periodontitis. The acute phase of these diseases involves neutrophilic infiltration. Neutrophil activation and recruitment to inflammatory sites are crucial in both protection against bacterial infection and the induction of hystotoxic damage. Activated neutrophils release several enzymes, including elastase and myeloperoxidase (MPO), which contribute to tissue injury via direct toxic actions, the generation of oxidants and inactivation of protective factors, such as alpha1-antitrypsin (alpha1-AT). In the present study, we investigated whether chlorhexidine can modulate neutrophil-mediated histotoxicity. 2. Human primary neutrophils were isolated from healthy donors. Inactivation of alpha1-AT by neutrophils or hypochlorous acid (HOCl) was evaluated by spectrophotometry and sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis of its capacity to complex with porcine pancreatic elastase (PPE). Neutrophil generation of HOCl, superoxide anion and MPO release were assessed spectrophometrically. 3. Chlorhexidine (0, 0.5, 1, 5 and 10 micromol/L) dose-dependently prevented HOCl-induced inactivation of alpha1-AT and reduced HOCl recovery from phorbol myristate acetate (PMA)-treated human neutrophils, but did not inhibit superoxide anion and MPO release. Chlorhexidine directly inhibited HOCl recovery from neutrophils and HOCl-induced inactivation of alpha1-AT in a cell-free assay. Accordingly, chlorhexidine reversed HOCl-mediated inhibition of alpha1-AT capacity to complex with PPE. 4. These data suggest that chlorhexidine prevents neutrophil-induced alpha1-AT inactivation via a direct inhibitory action on HOCl. Although highly speculative, the present study indicates that chlorhexidine may protect inflamed tissues not only through its antimicrobial properties, but also via a direct anti-inflammatory effect on neutrophil toxic products.

Sulphasalazine accelerates apoptosis in neutrophils exposed to immune complex: Role of caspase pathway.

1. Neutrophils release several histotoxic molecules that cause tissue injury. Neutrophil apoptosis is a crucial process that governs the persistence of inflammatory disorders and tissue damage. Thus, in the present study, we investigated whether the anti-inflammatory drug sulphasalazine (SSZ) affects neutrophil apoptosis in the presence of insoluble immune complex (IC). 2. Neutrophils were obtained from healthy donors. Neutrophils were resuspended in incubation medium and incubated for 2-12 h with or without 10, 30 or 100 micromol/L SSZ and 25 microg/mL IC. In some experiments, cells were co-incubated with 20 micromol/L Z-IETD-fmk (a caspase 8 inhibitor) or 20 micromol/L Z-LEHD-fmk (a caspase 9 inhibitor). Apoptosis was evaluated morphologically on cytological preparations stained with May-Grünwald-Giemsa as well as by flow cytometry analysis of annexin V and propidium iodide staining. Caspase 3 activity was determined spectrophotometrically. 3. At 100 micromol/L, SSZ significantly accelerated IC-induced neutrophil apoptosis. Treatment of neutrophils with 20 micromol/L of the caspase 8 or 9 inhibitors Z-IETD-fmk or Z-LEHD-fmk, respectively, demonstrated that the SSZ-induced pro-apoptotic effect was mediated by a caspase 8- but not caspase 9-dependent pathway. The caspase 3 activity assay showed that treatment with 100 micromol/L SSZ increased caspase 3 activation. 4. In conclusion, the results of the present study indicate that it is possible that the molecular mechanism underlying SSZ protection against neutrophil-mediated tissue injury inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases, involves a caspase 8-dependent pathway.